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Current Research and Scholarly Interests

Dr. Ketter has done extensive research into the etiology, phenomenology, and treatment of bipolar disorder. His etiologic research has focused on the use of brain imaging methods such as magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) to better understand the neurobiology of mood disorders and to explore the possibility of using these techniques to more effectively target treatments for patients with bipolar disorder. His phenomenologic research has focused on the development and course of bipolar disorder in late adolescence and young adulthood, particularly in college students, and links between creativity, temperament, and mood disorders. His research into treatment has involved clinical trials of novel medications and combinations of medications in the treatment of bipolar disorder, with an emphasis on the use of anticonvulsants.

Clinical Trials

Estrogen Use in Protection From Cognitive DeclineNot Recruiting

This study is designed to assess the effects of estrogen therapy among postmenopausal women
at risk for cognitive decline.

Abstract

Current irritability is associated with greater retrospective and current bipolar disorder (BD) illness severity; less is known about prospective longitudinal implications of current irritability. We examined relationships between current irritability and depressive recurrence and recovery in BD.Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form during follow-up during up to 2 years of naturalistic treatment. Prevalence and clinical correlates of any current irritability in depressed and recovered (euthymic ≥8 weeks) BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between current irritability and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators.Recovered BD outpatients with vs. without current irritability had significantly higher rates of 13/19 (68.4 %) other baseline unfavorable illness characteristics/current mood symptoms and hastened depressive recurrence (Log-Rank p = 0.020), driven by lifetime history of anxiety disorder and prior year rapid cycling, and attenuated by history of psychosis. Depressed BD outpatients with vs. without current irritability had significantly higher rates of 7/19 (36.8 %) other unfavorable illness characteristics/current mood symptoms and delayed depressive recovery (Log-Rank p = 0.034), NOT mediated by any assessed parameter.Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.Current irritability was associated with hastened depressive recurrence and delayed depressive recovery in BD. Treatment studies targeting irritability may yield strategies to mitigate increased longitudinal depressive burden.

Abstract

Bipolar Disorder (BD) is a leading cause of disability worldwide and factors contributing to its burden include chronic relapsing course, comorbidity, suicide risk, and early age at onset (AAO). In particular, recent investigation has shown that BD onset may occur earlier than previously believed, even though whether BDI and II are different in such regard is still debated. Reduced samples may, moreover, limit the confidence in the published studies, with geographic issues, in turn, representing potentially conditioning factors. The present review was aimed to select and analyze large sample studies comparing AAO in BDI vs II patients.A PubMed literature search was performed, considering English-written articles published up to December 2015, comparing AAO in BDI vs II patients with sample size≥100 subjects per group.Seventeen studies were considered suitable for revision, with 8 studies reporting statistically significant differences and 9 not. Among studies reporting statistically significant differences, mostly conducted in Europe, 6 showed an earlier AAO in BDI, while 2 in BDII subjects.Only studies with large samples included, considering AAO as a continuous variable, and providing a comparison between the bipolar subtypes.Our findings suggest that AAO per se does not seem to reliably differentiate BDI from BDII patients and that such variable should likely be investigated in the context of other clinical characteristics, in order to assess its overall influence over BD course. Geographic factors may, in turn, play a potential role with future investigation warranted to further explore this specific issue.

Abstract

The objective of this study was to assess the strengths and limitations of a mixed bipolar depression definition made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by counting not only 'non-overlapping' mood elevation symptoms (NOMES) as in DSM-5, but also 'overlapping' mood elevation symptoms (OMES, psychomotor agitation, distractibility, and irritability).Among bipolar disorder (BD) out-patients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using more inclusive (≥3 NOMES/OMES) and less inclusive DSM-5 (≥3 NOMES) definitions.Among 153 depressed BD, counting not only NOMES but also OMES yielded a three-fold higher mixed depression rate (22.9% vs. 7.2%) and important statistically significant clinical correlates for mixed compared to pure depression (more lifetime anxiety disorder comorbidity, more current irritability, and less current antidepressant use), which were not significant using the DSM-5 threshold.To conclude, further studies with larger numbers of patients with DSM-5 bipolar mixed depression assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including efforts to ascertain whether or not OMES should count toward mixed depression.

Abstract

Assess strengths and limitations of mixed bipolar depression definitions made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by requiring fewer than three 'non-overlapping' mood elevation symptoms (NOMES).Among bipolar disorder (BD) out-patients assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using less inclusive (≥3 NOMES, DSM-5), more inclusive (≥2 NOMES), and most inclusive (≥1 NOMES) definitions.Among 153 depressed BD, compared to less inclusive DSM-5 threshold, our more and most inclusive thresholds, yielded approximately two- and five-fold higher mixed depression rates (7.2%, 15.0%, and 34.6% respectively), and important statistically significant clinical correlates for mixed compared to pure depression (e.g. more lifetime anxiety disorder comorbidity, more current irritability), which were not significant using the DSM-5 threshold.Further studies assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including assessing the extent to which enhanced statistical power vs. other factors contributes to more vs. less inclusive mixed bipolar depression thresholds having more statistically significant clinical correlates, and whether 'overlapping' mood elevation symptoms should be counted.

Abstract

Although current irritability and current/prior anxiety have been associated in unipolar depression, these relationships are less well understood in bipolar disorder (BD). We investigated relationships between current irritability and current/prior anxiety as well as other current emotions and BD illness characteristics.Outpatients referred to the Stanford Bipolar Disorders Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prevalence and clinical correlates of current irritability and current/prior anxiety and other illness characteristics were examined.Among 497 BD outpatients (239 Type I, 258 Type II; 58.1% female; mean ± SD age 35.6 ± 13.1 years), 301 (60.6%) had baseline current irritability. Patients with versus without current irritability had significantly higher rates of current anxiety (77.1% versus 42.9%, p

Abstract

Safe/well-tolerated treatments for bipolar I depression remain limited. We assessed safety/tolerability of adjunctive open-label armodafinil, a wakefulness-promoting agent evaluated in 3 acute, controlled efficacy studies with variable efficacy results.Completers of three 8-week, double-blind, placebo-controlled adjunctive armodafinil studies (150-200 mg/day added to ongoing stable maintenance doses of 1 or 2 protocol-defined mood stabilizers) in bipolar I depression could enter this 6-month, open-label extension study. Objectives included evaluation of safety/tolerability (primary) and efficacy (secondary).867 patients enrolled; 863 received ≥1 dose of armodafinil and 506 (58%) completed the 6-month study. Headache, insomnia, and anxiety were the most common adverse events (AEs) reported, whereas akathisia, nausea, sedation/somnolence, and weight increase were uncommon. Mean measures assessing emergence of mania, anxiety, insomnia, or suicidality showed no worsening. Discontinuations due to AEs occurred in 57 (7%) patients. Serious AEs occurred in 27 (3%) patients and were considered treatment-related in 8 (1%) patients. Depressive symptoms improved over the 6 months, as did patient functioning.Lack of placebo control.Adjunctive armodafinil was generally safe and well tolerated over 6 months of open-label treatment at 150-200 mg/day when taken with protocol-defined mood stabilizers for bipolar I depression. This 6-month open-label study suggested that armodafinil augmentation of bipolar maintenance therapies may have a favorable risk profile and may improve depressive symptoms in some patients with bipolar I depression.

Abstract

Although bipolar disorder (BD) is a common recurrent condition with highly heterogeneous illness course, data are limited regarding clinical implications of interactions between gender and onset age. We assessed relationships between onset age and demographic/illness characteristics among BD patients stratified by gender.Demographic and unfavorable illness characteristics, descriptive traits, and clinical correlates were compared in 502 patients from Stanford University BD Clinic patients enrolled in the Systematic Treatment Enhancement Program for BD between 2000 and 2011, stratified by gender, across pre-, peri-, and post-pubertal (<12, 13-16, and >17 years, respectively) onset-age subgroups.Among 502 BD patients, 58.2% were female, of whom 21.9% had pre-pubertal, 30.7% peri-pubertal, and 47.4% post-pubertal onset. Between genders, although demographics, descriptive characteristics, and most clinical correlates were statistically similar, there were distinctive onset-age related patterns of unfavorable illness characteristics. Among females, rates of 6/8 primary unfavorable illness characteristics were significantly higher in pre-pubertal and peri-pubertal compared to post-pubertal onset patients. However, among males, rates of only 3/8 unfavorable illness characteristics were significantly higher in only pre-pubertal versus post-pubertal onset patients, and none between peri-pubertal versus post-pubertal onset patients.Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability, onset age based on retrospective recall.We describe different phenotypic presentations across age at illness onset groups according to gender. Among females and males, peri-pubertal and post-pubertal onset age groups were more different and more similar, respectively. Further investigation is warranted to assess implications of gender-by-onset-age interactions to more accurately delineate distinctive BD phenotypes.

Abstract

The aim of this study was to evaluate the safety and tolerability of 6 months of open-label, uncontrolled extension treatment with lurasidone in patients with a diagnosis of bipolar depression who completed 6 weeks of acute treatment.Patients completing 6 weeks of double-blind placebo-controlled treatment with either lurasidone monotherapy (one study) or adjunctive therapy with lithium or valproate (two studies), were treated for 6 months with flexible doses of lurasidone, 20-120 mg/day, in an open-label, uncontrolled extension study (N = 813; monotherapy, 38.9%; adjunctive therapy, 61.1%). Changes in safety parameters were calculated from double-blind, acute-phase baseline to month 6 of the extension phase, using a last observation carried forward (LOCF endpoint) analysis.Five hundred fifty-nine of 817 (68.4%) patients completed the extension study. In the monotherapy and adjunctive therapy groups, 6.9 and 9.0%, respectively, discontinued due to an adverse event. For the monotherapy and adjunctive therapy groups, respectively, changes from double-blind baseline to month 6 were +0.8 and +0.9 kg for weight (mean), 0.0 and +2.0 mg/dL for total cholesterol (median), +5.0 and +5.0 mg/dL for triglycerides (median), -1.0 and 0.0 mg/dL for glucose (median); -22.6 and -21.7 for Montgomery-Asberg Depression Rating Scale (MADRS; mean); whereas change from open-label baseline to month 6 were +0.85 and +0.88 kg for weight (mean), and -6.9 and -6.5 for MADRS (mean).Six months of treatment with open-label lurasidone was safe and well tolerated with minimal effect on weight and metabolic parameters; continued improvement in depressive symptoms was observed.

Abstract

To assess second-generation antipsychotic (SGA) use, demographics, and clinical correlates in patients with bipolar I disorder (BDI) versus bipolar II disorder (BDII).Stanford Bipolar Disorder (BD) Clinic outpatients enrolled during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Current SGA use, demographics, and clinical correlates were assessed for BDI versus BDII.Among 503 BD outpatients, in BDI versus BDII, SGA use was more than twice as common (44.0% versus 21.2%), and doses were approximately twice as high. BDI patients taking (N = 107) versus not taking (N = 136) SGAs less often had current full time employment and college degree; and more often had lifetime psychiatric hospitalization, current depression, and current complex pharmacotherapy, and had a higher mean current Clinical Global Impression for Bipolar Version Overall Severity score, and these persisted significantly after covarying for employment and education. Prior psychiatric hospitalization was the most robust correlate of SGA use in BDI patients. In contrast, these demographic and clinical correlates of SGA use were not statistically significant among patients with BDII, although BDII (but not BDI) patients taking (N = 55) versus not taking (N = 205) SGAs were more likely to have current mood stabilizer use (67.3% versus 51.7%).American tertiary bipolar disorder clinic referral sample, cross-sectional design.Current SGA use was robustly associated with prior psychiatric hospitalization in BDI and to a more limited extent with current mood stabilizer use in BDII. SGA use associations with other unfavorable illness characteristics in BDI were less robust.

Abstract

Few brief, self-report measures exist that can reliably predict adverse suicidality outcomes in patients with BD. This study utilized the Concise Health Risk Tracking Self-Report (CHRT) to assess suicidality in patients with BD and examined its psychometric performance, clinical correlates, and prospective value in predicting adverse events related to suicidality.The CHRT was administered at baseline and follow-up to 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. The Columbia Suicide Severity Rating Scale (CSSRS) was used at baseline to assess lifetime history of suicide attempts and related behaviors. Clinician-rated measures of mood (Bipolar Inventory of Symptoms Scale) and bipolar symptoms (Clinical Global Impressions-Bipolar Version) were conducted at baseline and follow-up.The CHRT showed excellent internal consistency and construct validity and was highly correlated with clinician ratings of depression, anxiety, and overall functioning at baseline and throughout the study. Baseline CHRT scores significantly predicted risk of subsequent suicidality-related Serious Adverse Events (sSAEs), after controlling for mood and comorbidity. Specifically, the hazard of a sSAE increased by 76% for every 10-point increase in baseline CHRT score. Past history of suicide attempts and related behaviors, as assessed by the CSSRS, did not predict subsequent sSAEs.The CSSRS was used to assess static risk factors in terms of past suicidal behaviors and may have been a more powerful predictor over longer-term follow-up.The CHRT offers a quick and robust self-report tool for assessing suicidal risk and has important implications for future research and clinical practice.

Abstract

Bipolar disorder is among the 10 most disabling medical conditions worldwide. While lithium has been used extensively for bipolar disorder since the 1970s, second-generation antipsychotics (SGAs) have supplanted lithium since 1998. To date, no randomized comparative-effectiveness study has compared lithium and any SGA.Within the duration of the study (September 2010-September 2013), participants with bipolar I or II disorder (DSM-IV-TR) were randomized for 6 months to receive lithium (n = 240) or quetiapine (n = 242). Lithium and quetiapine were combined with other medications for bipolar disorder consistent with typical clinical practice (adjunctive personalized treatment [APT], excluding any SGA for the lithium + APT group and excluding lithium or any other SGA for the quetiapine + APT group). Coprimary outcome measures included Clinical Global Impressions-Efficacy Index (CGI-EI) and necessary clinical adjustments, which measured number of changes in adjunctive personalized treatment. Secondary measures included a full range of symptoms, cardiovascular risk, functioning, quality of life, suicidal ideation and behavior, and adverse events.Participants improved across all measures, and over 20% had a sustained response. Primary (CGI-EI, P = .59; necessary clinical adjustments, P = .15) and secondary outcome changes were not statistically significantly different between the 2 groups. For participants with greater manic/hypomanic symptoms, CGI-EI changes were significantly more favorable with quetiapine + APT (P = .02). Among those with anxiety, the lithium + APT group had fewer necessary clinical adjustments per month (P = .02). Lithium was better tolerated than quetiapine in terms of the burden of side effects frequency (P = .05), intensity (P = .01), and impairment (P = .01).Despite adequate power to detect clinically meaningful differences, we found outcomes with lithium + APT and quetiapine + APT were not significantly different across 6 months of treatment for bipolar disorder.ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

Abstract

To examine the effects of treatment on functioning impairments and quality of life and assess baseline functioning and employment status as predictors of treatment response in symptomatic individuals from the Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (Bipolar CHOICE) study.Bipolar CHOICE was an 11-site, 6-month randomized effectiveness study comparing lithium to quetiapine, each with adjunctive personalized treatments (APTs). We examined post hoc (1) the effects of treatment on functioning, (2) how changes in functioning differed between treatment responders and nonresponders, and (3) whether functioning and employment status mediated treatment response in 482 participants with DSM-IV-TR bipolar I or II disorder from September 2010 to September 2013.Treatment was associated with significant improvements in functioning and quality of life, regardless of treatment group (P values < .0001). Responders showed greater improvements in quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire P values < .05) and functioning (Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool P values < .05) than nonresponders. Unemployed or disabled participants at baseline had significantly greater illness severity at baseline than employed participants (P values < .05). Over the study duration, employed participants reported greater improvements in physical health and quality of life in leisure activities than both unemployed and disabled participants (P values < .05). Individuals who saw greater improvement in functioning and quality of life tended to show greater improvements in depressive and anxiety symptoms (P values ≤ .0001), as well as overall illness severity (P values < .001). Early (8 weeks) and very early (4 weeks) clinical changes in mood symptoms predicted changes in functioning and quality of life at 6 months (P values < .001).Prior disability status was associated with a worse treatment response and prospective illness course. Results implicate functioning and employment status as important markers of illness severity and likelihood of recovery in bipolar disorder, suggesting that interventions that target functional impairment may improve outcomes.ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

Abstract

In this post-hoc analysis, rates of remission and recovery were evaluated in patients with bipolar depression treated with lurasidone.Outpatients meeting DSM-IV-TR criteria for bipolar I depression, were randomized to 6 weeks of once-daily, double-blind treatment with lurasidone 20-60mg, lurasidone 80-120mg or placebo, followed by a 6-month, open-label, flexible-dose, lurasidone continuation study. Recovery was defined as meeting criteria for combined symptomatic remission (Montgomery-Asberg Depression Rating Scale total score ≤12) and functional remission (all Sheehan Disability Scale domain scores ≤3) sustained for at least 3 months in the 6-month continuation study.A significantly higher proportion of lurasidone-treated patients met criteria for combined symptomatic remission and functional remission (33.3%, 91/273) compared to the placebo group (21.0%, 30/143, p<0.05, NNT=9) at the 6-week study endpoint. In the 6-month continuation study, the proportion of lurasidone-treated patients achieving sustained recovery was 60.7% (85/140) and 44.9% (31/69), for patients who continued lurasidone treatment and who switched from placebo to lurasidone, respectively.The definition of recovery used has not been previously validated and the analysis was post hoc. Lack of a control group in the continuation study limits data interpretation.Recovery in patients with bipolar depression was assessed based on rates of combined symptomatic and functional remission sustained over time. A majority of patients initially treated with lurasidone in the acute phase achieved recovery status in the continuation study. Treatment with lurasidone (vs. placebo) earlier in the course of the bipolar depressive episode increased the likelihood of subsequent recovery.

Abstract

The strengths and limitations of considering childhood-and adolescent-onset bipolar disorder (BD) separately versus together remain to be established. We assessed this issue.BD patients referred to the Stanford Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Patients with childhood- and adolescent-onset were compared to those with adult-onset for 7 unfavorable bipolar illness characteristics with replicated associations with early-onset patients.Among 502 BD outpatients, those with childhood- (<13 years, N=110) and adolescent- (13-18 years, N=218) onset had significantly higher rates for 4/7 unfavorable illness characteristics, including lifetime comorbid anxiety disorder, at least ten lifetime mood episodes, lifetime alcohol use disorder, and prior suicide attempt, than those with adult-onset (>18 years, N=174). Childhood- but not adolescent-onset BD patients also had significantly higher rates of first-degree relative with mood disorder, lifetime substance use disorder, and rapid cycling in the prior year. Patients with pooled childhood/adolescent - compared to adult-onset had significantly higher rates for 5/7 of these unfavorable illness characteristics, while patients with childhood- compared to adolescent-onset had significantly higher rates for 4/7 of these unfavorable illness characteristics.Caucasian, insured, suburban, low substance abuse, American specialty clinic-referred sample limits generalizability. Onset age is based on retrospective recall.Childhood- compared to adolescent-onset BD was more robustly related to unfavorable bipolar illness characteristics, so pooling these groups attenuated such relationships. Further study is warranted to determine the extent to which adolescent-onset BD represents an intermediate phenotype between childhood- and adult-onset BD.

Abstract

Few prospective studies examine the impact of ethnicity or race on outcomes with lithium for bipolar disorder. This exploratory study examines differences in lithium response and treatment outcomes in Hispanics, African Americans, and non-Hispanic whites with bipolar disorder in the Lithium Treatment Moderate Dose Use Study (LiTMUS).LiTMUS was a six-site randomized controlled trial of low-dose lithium added to optimized treatment (OPT; personalized, evidence-based pharmacotherapy) vs. OPT alone in outpatients with bipolar disorder. Of 283 participants, 47 African Americans, 39 Hispanics, and 175 non-Hispanic whites were examined. We predicted minority groups would have more negative medication attitudes and higher attrition rates, but better clinical outcomes.African Americans in the lithium group improved more on depression and life functioning compared to whites over the 6 month study. African Americans in the OPT only group had marginal improvement on depression symptoms. For Hispanics, satisfaction with life did not significantly improve in the OPT only group, in contrast to whites and African Americans who improved over time on all measures. Attitudes toward medications did not differ across ethnic/racial groups.African Americans show some greater improvements with lithium than non-Hispanic whites, and Hispanics showed more consistent improvements in the lithium group. The impact of low-dose lithium should be studied in a larger sample as there may be particular benefit for African Americans and Hispanics. Given that the control group (regardless of ethnicity/race) had significant improvements, optimized treatment may be beneficial for any ethnic group.

Abstract

To determine if a treatment for interepisode bipolar disorder I patients with insomnia improves mood state, sleep, and functioning.Alongside psychiatric care, interepisode bipolar disorder I participants with insomnia were randomly allocated to a bipolar disorder-specific modification of cognitive behavior therapy for insomnia (CBTI-BP; n = 30) or psychoeducation (PE; n = 28) as a comparison condition. Outcomes were assessed at baseline, the end of 8 sessions of treatment, and 6 months later. This pilot was conducted to determine initial feasibility and generate effect size estimates.During the 6-month follow-up, the CBTI-BP group had fewer days in a bipolar episode relative to the PE group (3.3 days vs. 25.5 days). The CBTI-BP group also experienced a significantly lower hypomania/mania relapse rate (4.6% vs. 31.6%) and a marginally lower overall mood episode relapse rate (13.6% vs. 42.1%) compared with the PE group. Relative to PE, CBTI-BP reduced insomnia severity and led to higher rates of insomnia remission at posttreatment and marginally higher rates at 6 months. Both CBTI-BP and PE showed statistically significant improvement on selected sleep and functional impairment measures. The effects of treatment were well sustained through follow-up for most outcomes, although some decline on secondary sleep benefits was observed.CBTI-BP was associated with reduced risk of mood episode relapse and improved sleep and functioning on certain outcomes in bipolar disorder. Hence, sleep disturbance appears to be an important pathway contributing to bipolar disorder. The need to develop bipolar disorder-specific sleep diary scoring standards is highlighted.

Abstract

This study examines characteristics of individuals with bipolar disorder who sought psychotherapy versus those who did not.Bipolar CHOICE was an 11-site comparative effectiveness study of lithium versus quetiapine in symptomatic outpatients (N = 482) with bipolar disorder. At baseline, participants' psychotherapy use within the past 3 months, mood, functioning, and overall health were assessed. Logistic regressions were used to test whether psychotherapy users and non-users differed on various demographic and clinical variables at baseline. Mixed-effects regression was used to determine whether psychotherapy groups differed on response to treatment over the 6-month study. Kaplan-Meier plots and log-rank tests were employed to test whether there were any differences in time to recovery (CGI-BP ≤ 2 for at least 8 weeks) between the groups.Thirty one percent of participants reported using psychotherapy services. Psychotherapy users reported greater medication side effect burden than non-users and were more likely to have moderate to high suicide risk and at least one anxiety disorder. Participants not utilizing medications or psychotherapy had greater mania symptom severity, were younger, and less educated than medication only users. Medication only users were more likely to be married than the other participants.These data suggest that a minority of individuals with bipolar disorder attend psychotherapy services, and those that do have greater illness burden.

Abstract

Neurocognitive impairment in schizophrenia has been recognized for more than a century. In contrast, only recently have significant neurocognitive deficits been recognized in bipolar disorder. Converging data suggest the importance of cognitive problems in relation to quality of life in bipolar disorder, highlighting the need for treatment and prevention efforts targeting cognition in bipolar patients. Future treatment trials targeting cognitive deficits will be met with methodological challenges due to the inherent complexity and heterogeneity of the disorder, including significant diagnostic comorbidities, the episodic nature of the illness, frequent use of polypharmacy, cognitive heterogeneity, and a lack of consensus regarding measurement of cognition and outcome in bipolar patients. Guidelines for use in designing future trials are needed.The members of the consensus panel (each of the bylined authors) were selected based upon their expertise in bipolar disorder. Dr Burdick is a neuropsychologist who has studied cognition in this illness for 15 years; Drs Ketter, Calabrese, and Goldberg each bring considerable expertise in the treatment of bipolar disorder, both within and outside of controlled clinical trials. This consensus statement was derived from work together at scientific meetings (eg, symposium presentation at the 2014 Annual Meeting of the American Society of Clinical Psychopharmacology, among others) and ongoing discussions by conference call. With the exception of the public presentations on this topic, these meetings were closed to outside participants.A literature review was undertaken by the authors to identify illness-specific challenges relevant to the design and conduct of treatment trials targeting neurocognition in bipolar disorder. Expert opinion from each of the authors guided the consensus recommendations.Consensus recommendations, reached by unanimous opinion of the authors, are provided here as a preliminary guide for future trial design. Recommendations comprise exclusion of certain syndromal-level comorbid diagnoses and current affective instability, restrictions on numbers and types of medications, and use of prescreening assessment to ensure enrollment of subjects with adequate objective evidence of baseline cognitive impairment.Clinical trials to address cognitive deficits in bipolar disorder face distinctive design challenges. As such trials move from proof-of-concept to confirmation of clinical efficacy, it will be important to incorporate distinctive design modifications to adequately address these challenges and increase the likelihood of demonstrating cognitive remediation effects. The field is now primed to address these challenges, and a comprehensive effort to formalize best practice guidelines will be a critically important next step.

Abstract

Individuals with bipolar disorder have high rates of other medical comorbidity, which is associated with higher mortality rates and worse course of illness. The present study examined common predictors of medical comorbidity.The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE) enrolled 482 participants with bipolar I or bipolar II disorder in a six-month, randomized comparative effectiveness trial. Baseline assessments included current and lifetime DSM-IV-TR diagnoses, demographic information, psychiatric and medical history, severity of psychiatric symptoms, level of functioning, and a fasting blood draw. Medical comorbidities were categorized into two groups: cardiometabolic (e.g., diabetes, hyperlipidemia, and metabolic syndrome) and non-cardiovascular (e.g., seizures, asthma, and cancer). Additionally, we looked at comorbid substance use (e.g., smoking and drug dependence).We found that 96.3% of participants had at least one other medical comorbidity. Older age predicted a greater likelihood of having a cardiometabolic condition. Early age of onset of bipolar symptoms was associated with a lower chance of having a cardiometabolic condition, but a greater chance of having other types of medical comorbidity. Additional predictors of other medical comorbidities in bipolar disorder included more time spent depressed, less time spent manic/hypomanic, and longer duration of illness. Medications associated with weight gain were associated with low high-density lipoprotein and abnormal triglycerides.There appears to be a substantial medical burden associated with bipolar disorder, highlighting the need for collaborative care among psychiatric and general medical providers to address both psychiatric and other medical needs concomitantly in this group of patients.

Abstract

Benzodiazepines are widely prescribed for patients with bipolar disorders in clinical practice, but very little is known about the subtypes of patients with bipolar disorder or aspects of bipolar illness that contribute most to benzodiazepine use. We examined the prevalence of and factors associated with benzodiazepine use among 482 patients with bipolar I or II disorder enrolled in the Bipolar CHOICE study. Eighty-one subjects were prescribed benzodiazepines at study entry and were considered benzodiazepine users. Stepwise logistic regression was used to model baseline benzodiazepine use versus nonuse, using entry and exit criteria of P < 0.1. In bivariate analyses, benzodiazepine users were prescribed a significantly higher number of other psychotropic medications and were more likely to be prescribed lamotrigine or antidepressants as compared with benzodiazepine nonusers. Benzodiazepine users were more likely to have a diagnosis of bipolar I disorder and comorbid anxiety disorder, but not comorbid alcohol or substance use disorders. Benzodiazepine users also had experienced more anxiety and depressive symptoms and suicidality, but not irritability or manic symptoms, than did benzodiazepine nonusers. In the multivariate model, anxiety symptom level (regardless of diagnosis), lamotrigine use, number of concomitant psychotropic medications, college education, and high household income predicted benzodiazepine use. Benzodiazepine use in patients with bipolar disorders is associated with greater illness complexity as indicated by a higher number of concomitant psychotropic medications and higher anxiety symptom burden, regardless of a comorbid anxiety disorder diagnosis. Demographic factors were also important determinants of benzodiazepine use, which may be related to access to care and insurance coverage for benzodiazepines.

Abstract

In the 2010s, advances in the treatment of bipolar disorder slowed, with only 1 agent approved by the US Food and Drug Administration (FDA) for acute bipolar I depression (in 2013), compared to the robust progress in the 2000s, during which 7 agents were approved for acute mania, 2 for acute bipolar depression, and 6 for bipolar disorder preventive treatment. This slowing of progress may have been in part due to decreased pharmaceutical company enthusiasm for developing compounds for psychiatric indications, as well as the tendency for periods of consolidation (development of derivative and better-tolerated treatments) to follow periods of rapid advances (development of efficacious novel treatments) in pharmacotherapy advancement.

Abstract

Bipolar disorder presents with diverse clinical manifestations. Numerous investigators have sought to identify variables that may predict a more severe illness course.With the objective of studying the clinical characteristics of bipolar patients between South and North America, a comparison was performed between a sample from Argentina (n = 449) and a sample from the United States (n = 503) with respect to demographics and clinical characteristics, including presence of comorbidities.The Argentinian sample had more unfavorable demographics and higher rates of prior psychiatric hospitalization and prior suicide attempt but a better social outcome. However, the sample from the United States had a higher rate of prior year rapid cycling, as well as younger bipolar disorder onset age (mean ± SD, 17.9 ± 8.4 vs. 27.1 ± 11.4 years) and more severe clinical morbidity, though there was no significant difference in terms of the total duration of the illness. Argentinian compared to American patients were taking more mood stabilizers and benzodiazepines/hypnotics, but fewer antipsychotics and other psychotropic medications, when considering patients in aggregate as well as when stratifying by illness subtype (bipolar I versus bipolar II) and by illness onset age (≤21 vs. >21 years). However, there was no significant difference in rate of antidepressant prescription between the two samples considered in aggregate.Although possessing similar illness durations, these samples presented significant clinical differences and distinctive prescription patterns. Thus, though the Argentinian compared to North American patients had more unfavorable demographics, they presented a better social outcome and, in several substantive ways, more favorable illness characteristics. In both samples, early onset (age ≤ 21 years) was a marker for poor prognosis throughout the illness course, although this phenomenon appeared more robust in North America.

Abstract

Bipolar depression is more pervasive than mania, but has fewer evidence-based treatments.Using data from multicenter, randomized, double-blind, placebo-controlled trials and meta-analyses, we assessed the number needed to treat (NNT) for response and the number needed to harm (NNH) for selected side effects for older and newer acute bipolar depression treatments.The 2 older FDA-approved treatments for bipolar depression, olanzapine-fluoxetine combination (OFC) and quetiapine (QTP) monotherapy, were efficacious (response NNT=4 for OFC, NNT=6 for QTP), but similarly likely to yield harms (OFC weight gain NNH=6; QTP sedation/somnolence NNH=5). Commonly used unapproved agents (lamotrigine monotherapy and adjunctive antidepressants) tended to be well-tolerated (with double-digit NNHs), although this advantage was at the cost of inadequate efficacy (response NNT=12 for lamotrigine, NNT=29 for antidepressants). In contrast, the newly approved agent lurasidone was not only efficacious (response NNT=5 for monotherapy, NNT=7 as adjunctive therapy), but also had enhanced tolerability (NNH=15 for akathisia [monotherapy], NNH=16 for nausea [adjunctive]). Although adjunctive armodafinil appeared well tolerated, its efficacy in bipolar depression has not been consistently demonstrated in randomized controlled trials.NNT and NNH are categorical metrics; only selected NNHs were assessed; limited generalizability of efficacy (versus effectiveness) studies.For acute bipolar depression, older approved treatments may have utility in high-urgency situations, whereas lamotrigine and antidepressants may have utility in low-urgency situations. Newly approved lurasidone may ultimately prove useful in diverse situations. New drug development needs to focus on not only efficacy but also on tolerability.

Abstract

Bipolar disorder is characterized by debilitating episodes of depression and mood elevation (mania or hypomania). For most patients, depressive symptoms are more pervasive than mood elevation or mixed symptoms, and thus have been reported in individual studies to impose a greater burden on affected individuals, caregivers, and society. This article reviews and compiles the literature on the prevalence and burden of syndromal as well as subsyndromal presentations of depression in bipolar disorder patients.The PubMed database was searched for English-language articles using the search terms "bipolar disorder," "bipolar depression," "burden," "caregiver burden," "cost," "costs," "economic," "epidemiology," "prevalence," "quality of life," and "suicide." Search results were manually reviewed, and relevant studies were selected for inclusion as appropriate. Additional references were obtained manually from reviewing the reference lists of selected articles found by computerized search.In aggregate, the findings support the predominance of depressive symptoms compared with mood elevation/mixed symptoms in the course of bipolar illness, and thus an overall greater burden in terms of economic costs, functioning, caregiver burden, and suicide.This review, although comprehensive, provides a study-wise aggregate (rather than a patient-wise meta-analytic) summary of the relevant literature on this topic.In light of its pervasiveness and prevalence, more effective and aggressive treatments for bipolar depression are warranted to mitigate its profound impact upon individuals and society. Such studies could benefit by including metrics not only for mood outcomes, but also for illness burden.

Abstract

The amygdala and hippocampus - two structures intimately associated with mood and cognition - have been reported to exhibit altered neural activity or volume in affective disorders. We hypothesized the amygdala and hippocampus would show altered and differential patterns of connectivity in patients with bipolar (BPs) and unipolar (UPs) disorder compared to healthy volunteers.Thirty BPs, 34 UPs, and 66 healthy volunteers were imaged using F-18-fluorodeoxyglucose and positron emission tomography while performing an auditory continuous performance task (CPT). Normalized mean activity of the amygdala and hippocampus was correlated with the rest of the brain.In BPs, the amygdalae displayed exaggerated positive metabolic correlations with prefrontal and ventral striatal areas, while the hippocampus showed a paucity of normal inter-relations compared to controls. In contrast, in UPs the amygdala was significantly negatively correlated with prefrontal and anterior cingulate cortex, while the hippocampus was significantly more positively correlated to these same prefrontal areas.During a simple cognitive task, the functional connectivity of the amygdala and hippocampus, regions usually associated with emotion and memory regulation, was substantially different in affective illness compared to healthy controls whether or not there were baseline abnormalities in these areas. These striking differences in functional connectivity of amygdala and hippocampus should be further explored in ill and well states and using more specific emotion and cognitive evocative tasks.

Abstract

Little is known about the longer-term effects of adjunctive benzodiazepines on symptom response during treatment in patients with bipolar disorders.The study sample consisted of 482 patients with bipolar I or II disorder enrolled in a 6-month, randomized, multi-site comparison of lithium- and quetiapine-based treatment. Changes in clinical measures (BISS total and subscales, CGI-BP, and CGI-Efficacy Index) were compared between participants who did and did not receive benzodiazepine treatment at baseline or during follow-up. Selected outcomes were also compared between patients who did and did not initiate benzodiazepines during follow-up using stabilized inverse probability weighted analyses.Significant improvement in all outcome measures occurred within each benzodiazepine exposure group. Benzodiazepine users (at baseline or during follow-up) experienced significantly less improvement in BISS total, BISS irritability, and CGI-BP scores than did benzodiazepine non-users. There were no significant differences in these measures between patients who did and did not initiate benzodiazepines during follow-up in the weighted analyses. There was no significant effect of benzodiazepine use on any outcome measure in patients with comorbid anxiety or substance use disorders.This is a secondary analysis of data from a randomized effectiveness trial that was not designed to address differential treatment response according to benzodiazepine use.Adjunctive benzodiazepines may not significantly affect clinical outcome in lithium- or quetiapine-treated patients with bipolar I or II disorder over 6 months, after controlling for potential confounding factors.

Abstract

Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium.The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N = 283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire.We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms.Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

Abstract

This study was designed to identify genes whose expression in peripheral blood may serve as early markers for treatment response to lithium (Li) in patients with bipolar disorder. Although changes in peripheral blood gene-expression may not relate directly to mood symptoms, differences in treatment response at the biochemical level may underlie some of the heterogeneity in clinical response to Li. Subjects were randomized to treatment with (n=28) or without (n=32) Li. Peripheral blood gene-expression was measured before and 1month after treatment initiation, and treatment response was assessed after 6 months. In subjects treated with Li, 62 genes were differentially regulated in treatment responders and non-responders. Of these, BCL2L1 showed the greatest difference between Li responders and non-responders. These changes were specific to Li responders (n=9), and were not seen in Li non-responders or patients treated without Li, suggesting that they may have specific roles in treatment response to Li.

Abstract

Brain-derived neurotrophic factor (BDNF) protein has been implicated in the pathophysiology of mood disorders, with early data suggesting that blood levels may vary by severity of mood symptoms. BDNF polymorphism, val66met, has also been implicated in mood disorders.Euthymic women with bipolar disorder (BD) (n=47) and healthy control women (n=26), ages 18-45, were clinically rated using the Montgomery-Asberg Depression Rating Scale (MADRS) and sampled for plasma BDNF concentration, with a subset undergoing genetic analysis for the val66met.BD and control groups did not differ on any demographic variables, nor in plasma BDNF levels or val66met polymorphism. Plasma BDNF concentration did not differ by val66met or BD subtype, nor was it correlated with age or illness duration. Within women with BD, lower plasma BDNF concentrations were significantly associated with higher MADRS scores, even after controlling for psychotropic medication use and illness duration.The sample was relatively small and exclusive to women, with further research needed to investigate the links between BDNF markers and mood symptom severity in both men and women.The study provides a gender-specific investigation of plasma BDNF levels and mood, and the results add further evidence of a significant interplay between BDNF markers and psychiatric symptomatology. Further, this association did not appear to be confounded by use of psychotropic medication. Studies with larger samples of both genders are needed to further delineate this relationship.

Abstract

Classic and second-generation antipsychotic mood stabilizers are recommended for treatment of bipolar disorder, yet there are no randomized comparative effectiveness studies that have examined the 'real-world' advantages and disadvantages of these medications.We describe the strategic decisions in the design of the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE). This article outlines the key issues and solutions the investigators faced in designing a clinical trial that would maximize generalizability and inform real-world clinical treatment of bipolar disorder.Bipolar CHOICE was a 6-month, multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. This study compares the effectiveness of quetiapine versus lithium, each with adjunctive personalized treatments (APTs). The co-primary outcomes selected are the overall benefits and harms of the study medications (as measured by the Clinical Global Impression-Efficacy Index) and the Necessary Clinical Adjustments (a measure of the number of medication changes). Secondary outcomes are continuous measures of mood, the Framingham General Cardiovascular Risk Score, and the Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT).The final study design consisted of a single-blind, randomized comparative effectiveness trial of quetiapine versus lithium, plus APT, across 10 sites. Other important study considerations included limited exclusion criteria to maximize generalizability, flexible dosing of APT medications to mimic real-world treatment, and an intent-to-treat analysis plan. In all, 482 participants were randomized to the study, and 364 completed the study.The potential limitations of the study include the heterogeneity of APT, selection of study medications, lack of a placebo-control group, and participants' ability to pay for study medications.We expect that this study will inform our understanding of the benefits and harms of lithium, a classic mood stabilizer, compared to quetiapine, a second-generation antipsychotic with broad-spectrum activity in bipolar disorder, and will provide an example of a well-designed and well-conducted randomized comparative effectiveness clinical trial.

Abstract

Bipolar disorder has been associated with elevated impulsivity - a complex construct subsuming multiple facets. We aimed to compare specific facets of impulsivity in bipolar disorder, including those related to key psychological correlates of the illness: reward sensitivity and strong emotion.Ninety-one individuals diagnosed with bipolar I disorder (inter-episode period) and 80 controls completed several well-validated impulsivity measures, including those relevant to reward (Fun-seeking subscale of the Behavioral Activation System scale) and emotion (Positive Urgency and Negative Urgency scales).Bipolar participants reported higher impulsivity scores than did controls on all of the impulsivity measures, except the Fun-seeking subscale of the Behavioral Activation System scale. Positive Urgency - a measure assessing the tendency to act impulsively when experiencing strong positive emotion - yielded the largest group differences: F(1,170) = 78.69, P

Abstract

The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls.Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone.Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively.Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.

Abstract

To assess mood stabilizer (MS) and second-generation antipsychotic (SGA) prescribing trends in bipolar disorder (BD) outpatients referred to a bipolar disorder specialty clinic over the past 12 years.BD outpatients referred to the Stanford University Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prescription rates for MSs and SGAs were compared during the first (2000-2005) and second (2006-2011) six years.Among 597 BD patients (mean±SD age 35.4±8.6 years; 58.1% female; 40.7% Type I, 43.6% Type II, and 15.7% Type Not Otherwise Specified; taking 2.6±1.7 prescription psychotropic medications), lamotrigine, quetiapine, and aripiprazole usage more than doubled, from 14.7% to 37.2% (p<0.0001), 7.2% to 19.7% (p<0.0001), and 3.1% to 10.9% (p=0.0003), respectively, while olanzapine and risperidone use decreased by more than half from 15.0% to 6.6% (p=0.0043), and from 8.7% to 3.8% (p=0.039), respectively. SGA use increased from 34.1% to 44.8% (p=0.013), although MS use continued to be more common (in 65.2% for 2006-2011). Use of other individual MSs and SGAs and MSs as a class did not change significantly.Over 12 years, in patients referred to a BD specialty clinic, lamotrigine, quetiapine, and aripiprazole use more than doubled, and olanzapine and risperidone use decreased by more than half. Tolerability (for lamotrigine, aripiprazole, olanzapine, and risperidone) more than efficacy (for quetiapine) differences may have driven these findings. Additional studies are needed to explore the relative influences of enhanced tolerability versus efficacy upon prescribing practices in BD patients.

Clinical assessment of lurasidone benefit and risk in the treatment of bipolar I depression using number needed to treat, number needed to harm, and likelihood to be helped or harmedJOURNAL OF AFFECTIVE DISORDERSCitrome, L., Ketter, T. A., Cucchiaro, J., Loebel, A.2014; 155: 20-27

Abstract

Prior to recent FDA approval of lurasidone for treatment of bipolar depression there were only two approved treatments for this condition (quetiapine and olanzapine-fluoxetine combination), and these were as likely to provide therapeutic benefit as adverse effects. We assessed the efficacy, safety, and tolerability of lurasidone for major depressive episodes associated with bipolar I disorder, using number needed to treat (NNT, for benefits), number needed to harm (NNH, for harms), and likelihood of being helped or harmed (LHH, ratio of NNH to NNT, for trade-offs between benefits vs. harms).Data was collected from two 6-week multicenter, randomized, double-blind, placebo-controlled, flexibly-dosed acute bipolar I depression studies, one using lurasidone monotherapy at 20-60mg/d or 80-120mg/d, and the other using lurasidone 20-120mg/d adjunctive to lithium or valproate. The NNT or NNH was calculated for lurasidone vs. placebo for the following dichotomous outcomes: response (≥50% reduction from baseline on Montgomery Asberg Depression Rating Scale (MADRS) total score); remission (final MADRS total score ≤12); discontinuation due to an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; and incidence of total cholesterol ≥240mg/dl, low-density lipoprotein cholesterol ≥160mg/dl, fasting triglycerides ≥200mg/dl and glucose ≥126mg/dl post-baseline.NNT vs. placebo for response was 5 for lurasidone monotherapy (both dose ranges) and 7 for adjunctive therapy. NNT vs. placebo for remission for lurasidone monotherapy was 6 for 20-60mg/d and 7 for 80-120mg/d and 7 for adjunctive lurasidone. NNH vs. placebo for discontinuation due to an AE for lurasidone monotherapy was 642 for 20-60mg/d and -181 for 80-120mg/d, and for adjunctive lurasidone was -54 (negative NNH denotes an advantage for lurasidone). Lurasidone was not associated with any clinically meaningful mean weight or metabolic changes compared to placebo; NNH vs. placebo for weight gain ≥7% was 29 for 20-60mg/d and 5550 for 80-120mg/d and 42 for adjunctive lurasidone. The three most frequently occurring AEs with the largest difference in incidence for lurasidone vs. placebo were nausea, akathisia, and somnolence, with NNH values for lurasidone vs. placebo ranging from 11 (nausea with lurasidone monotherapy 80-120mg/d) to 130 (somnolence with lurasidone monotherapy 20-60mg/d). LHH was substantially and consistently >1 (indicating benefit being more likely than harm) when contrasting response or remission vs. AEs or weight gain.Additional studies, including longer-term and open-label, "real world" data is needed to confirm the results reported here.NNT, NNH, and LHH help quantify relative benefits (efficacy) and harms (side effects), thus placing lurasidone findings in research studies into clinical perspective. Lurasidone, compared to other treatments approved for bipolar depression, yielded comparable benefits (all had single-digit NNT vs. placebo for response or remission), and less risk of harm (double-digit or greater NNHs with lurasidone compared to single-digit NNHs for sedation with quetiapine and for ≥7% weight gain with olanzapine-fluoxetine combination), and thus a substantially more favorable LHH (> or >1) with lurasidone monotherapy and adjunctive therapy, compared to quetiapine and olanzapine-fluoxetine combination (LHH

Abstract

The Mood Disorder Questionnaire (MDQ) has been translated to many languages and has been used in many countries as a screening instrument for bipolar disorder. The main objective of this study was to evaluate validity of the Thai version of the MDQ as a screening instrument for bipolar disorder in a psychiatric outpatient sample, and to determine its optimum question #1 item threshold value for bipolar disorder.The English language Mood Disorder Questionnaire (MDQ) was translated into Thai. The process involved back-translation, cross-cultural adaptation, field testing of the prefinal version, as well as final adjustments. Two hundred and fifty major depressive disorder outpatients were further assessed by the Thai version of the MDQ and the Thai version of the Mini International Neuropsychiatric Interview (MINI). During the assessment, reliability and validity analyses, and receiver operating characteristic curve (ROC) analysis were performed.The Thai version of the MDQ screening had adequate internal consistency (Cronbach's alpha =0.791, omega total =0.68, and omega hierarchical =0.69). The optimal question #1 item threshold value was at least five positive items, which yielded adequate sensitivity (76.5%), specificity (72.7%), positive predictive value (74.3%), and negative predictive value (75.0%). The ROC area under the curve (AUC) for this study was 0.82 (95% confidence interval: 0.70 to 0.90).The Thai version of the MDQ had some useful psychometric properties for screening for bipolar disorder in a mood disorder clinic setting, with a recommended question #1 item threshold value of at least five positive items.

Abstract

This study examined general medical illnesses and their association with clinical features of bipolar disorder.Data were cross-sectional and derived from the Lithium Treatment - Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥4 and <4 respectively.The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive-compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty-nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥35; 31%, n = 14).The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.

Abstract

The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Abstract

Bipolar depression represents the most difficult-to-treat phase of bipolar disorder, mood-stabilizing compounds and second-generation antipsychotics being only partially effective, whereas the use of antidepressants is highly controversial because of risks of inefficacy, switching, rapid cycling, and increased suicidality. Among various augmentative pharmacological treatments, compounds with dopamine-enhancing activity have been shown to be variably beneficial in the treatment of bipolar depression with drug-resistance features. In particular, pramipexole - a dopamine D2/D3 receptor agonist - showed antidepressant properties in bipolar depressed patients in both randomized-controlled trials and open acute and follow-up reports. The present review aims to provide an updated perspective on the use of adjunctive pramipexole in bipolar depression, taking into account randomized-controlled trials, as well as open naturalistic studies, with a specific focus on the evaluation of acute versus long-term data in terms of effectiveness and tolerability. Despite methodological differences, short-term studies support the acute efficacy and tolerability/safety of adjunctive pramipexole, whereas open extended observations seem to confirm the effectiveness of the compound, with some additional concern in terms of safety and tolerability issues. Adjunctive pramipexole may be a valid option in both the acute and the long-term treatment of drug-resistant bipolar depression, with possible superior tolerability in the short term.

Abstract

OBJECTIVE Bipolar disorder is a severe, chronic mental illness with a high incidence of medical and psychological comorbidities that make treatment and prevention of future episodes challenging. This study investigated the use of services among outpatients with bipolar disorder to further understanding of how to maximize and optimize personalization and accessibility of services for this difficult-to-treat population. METHODS The Lithium Treatment-Moderate Dose Use Study (LiTMUS) was a six-month multisite, comparative effectiveness trial that randomly assigned 283 individuals to receive lithium plus optimized care-defined as personalized, guideline-informed care-or optimized care without lithium. Relationships between treatment service utilization, captured by the Cornell Service Index, and demographic and illness characteristics were examined with generalized linear marginal models. RESULTS Analyses with complete data (week 12, N=246; week 24, N=236) showed that increased service utilization was related to more severe bipolar disorder symptoms, physical side effects, and psychiatric and general medical comorbidities. Middle-aged individuals and those living in the United States longer tended to use more services than younger individuals or recent immigrants, respectively. CONCLUSIONS These data suggest that not all individuals with bipolar disorder seek treatment services at the same rate. Instead, specific clinical or demographic features may affect the degree to which one seeks treatment, conveying clinical and public health implications and highlighting the need for specific approaches to correct such discrepancies. Future research is needed to elucidate potential moderators of service utilization in bipolar disorder to ensure that those most in need of additional services utilize them.

Abstract

This paper describes the development and use of the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making. The Bipolar Trials Network developed and implemented the MRTF in a comparative effectiveness study for bipolar disorder (LiTMUS). The MRTF was used to assess the frequency, types, and reasons for medication adjustments. Changes in treatment were operationalized by the metric Necessary Clinical Adjustments (NCA), defined as medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. Randomized treatment groups did not differ in rates of NCAs, however, responders had significantly fewer NCAs than non-responders. Patients who had more NCAs during their previous visit had significantly lower odds of responding at the current visit. For each one-unit increase in previous CGI-BP depression score and CGI-BP overall severity score, patients had an increased NCA rate of 13% and 15%, respectively at the present visit. Ten-unit increases in previous Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores resulted in an 18% and 14% increase in rates of NCAs, respectively. Patients with fewer NCAs had increased quality of life and decreased functional impairment. The MRTF standardizes the reporting and rationale for medication adjustments and provides an innovative metric for clinical effectiveness. As the first tool in psychiatry to track the types and reasons for medication changes, it has important implications for training new clinicians and examining clinical decision making. (ClinicalTrials.gov number NCT00667745).

Abstract

Individuals with bipolar disorder lead a sedentary lifestyle associated with worse course of illness and recurrence of symptoms. Identifying potentially modifiable predictors of exercise frequency could lead to interventions with powerful consequences on the course of illness and overall health.The present study examines baseline reports of exercise frequency of bipolar patients in a multi-site comparative effectiveness study of a second generation antipsychotic (quetiapine) versus a classic mood stabilizer (lithium). Demographics, quality of life, functioning, and mood symptoms were assessed.Approximately 40% of participants reported not exercising regularly (at least once per week). Less frequent weekly exercise was associated with higher BMI, more time depressed, more depressive symptoms, and lower quality of life and functioning. In contrast, more frequent exercise was associated with experiencing more mania in the past year and more current manic symptoms.Exercise frequency was measured by self-report and details of the exercise were not collected. Analyses rely on baseline data, allowing only for association analyses. Directionality and predictive validity cannot be determined. Data were collected in the context of a clinical trial and thus, it is possible that the generalizability of the findings could be limited.There appears to be a mood-specific relationship between exercise frequency and polarity such that depression is associated with less exercise and mania with more exercise in individuals with bipolar disorder. This suggests that increasing or decreasing exercise could be a targeted intervention for patients with depressive or mood elevation symptoms, respectively.

Abstract

OBJECTIVES: To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation. METHODS: Participants included 55 adults (age 18-65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ≥2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1-3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25). RESULTS: Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO. CONCLUSIONS: While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study.

Abstract

Bipolar depression is considered the most difficult-to-treat phase of bipolar disorder, in relation to its pervasiveness and efficacy and/or tolerability limitations of available treatments. Indeed, most mood stabilizers and atypical antipsychotics are not as effective in ameliorating depressive compared with manic symptoms, and entail substantial tolerability limitations. However, the use of antidepressants is highly controversial, as their efficacy appears less robust in bipolar compared with unipolar depression. In addition, antidepressants, in spite of generally having adequate somatic tolerability, in BD may be associated with a higher risk of manic/hypomanic switch, suicidality and rapid cycling. Among alternative pharmacological strategies, compounds with stimulant and pro-dopaminergic effects, such as methylphenidate, modafinil, armodafinil and pramipexole, have showed potential antidepressant activity, even though their use in clinical practice has been limited by the paucity of controlled evidence. This article seeks to review available evidence about the use of the aforementioned compounds in the treatment of bipolar depression. Findings from reviewed studies suggested that pro-dopaminergic compounds, such as pramipexole and stimulants/stimulant-like agents, deserve consideration as adjunctive therapies in bipolar depressed patients, at least in some subgroups of patients. Nevertheless, caution regarding their use is recommended as further clinical trials with larger samples and longer follow-up periods are necessary to clarify the roles of these medications in bipolar depression.

Efficacy and safety of armodafinil as an adjunctive therapy for the treatment of a major depressive episode associated with bipolar I disorderFrye, M. A., Ketter, T. A., Yang, R.WILEY-BLACKWELL.2013: 126-127

When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmedINTERNATIONAL JOURNAL OF CLINICAL PRACTICECitrome, L., Ketter, T. A.2013; 67 (5): 407-411

Abstract

Although great effort is made in clinical trials to demonstrate statistical superiority of one intervention vs. another, insufficient attention is paid regarding the clinical relevance or clinical significance of the observed outcomes. Effect sizes are not always reported. Available absolute effect size measures include Cohen's d, area under the curve, success rate difference, attributable risk and number needed to treat (NNT). Of all of these measures, NNT is arguably the most clinically intuitive and helps relate effect size difference back to real-world concerns of clinical practice. This commentary reviews the formula for NNT, and proposes acceptable values for NNT and its analogue, number needed to harm (NNH), using examples from the medical literature. The concept of likelihood to be helped or harmed (LHH), calculated as the ratio of NNH to NNT, is used to illustrate trade-offs between benefits and harms. Additional considerations in interpreting NNT are discussed, including the importance of defining acceptable response, adverse outcomes of interest, the effect of time, and the importance of individual baseline characteristics.

Abstract

Bipolar depression represents a high priority research field, due to its pervasiveness, and high economic and personal (suicidality, impaired function, quality of life) costs, and the limited evidence base to inform therapeutics. Mood stabilizers and second-generation antipsychotics for bipolar depression are commonly only partially effective, and their side-effects may overlap with depressive symptoms such as hypersomnia, daytime drowsiness, fatigue, psychomotor retardation, and weight gain. Moreover, the use of antidepressants in bipolar depression is controversial due to concerns regarding the risks of inefficacy or switching to mood elevation. Stimulants and related compounds such as modafinil and armodafinil have on occasion been used as adjuncts in bipolar depressed patients with encouraging results, but their use is limited by the paucity of systematic evidence of efficacy and safety. The present review aims to provide an updated perspective on the use of stimulants and stimulant-like medications in adult bipolar depression, considering not only recent randomized controlled trials, but also open naturalistic studies, in order to clarify the strengths and limitations of using these agents.

Abstract

Lithium salts, once the mainstay of therapy for bipolar disorder, have tolerability issues at a higher dosage that often limit adherence. The authors investigated the comparative effectiveness of more tolerable dosages of lithium as part of optimized personalized treatment (OPT).The authors randomly assigned 283 bipolar disorder outpatients to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder-Severity (CGI-BP-S) and "necessary clinical adjustments" (medication adjustments per month). Secondary outcome measures included mood symptoms and functioning. The authors also assessed sustained remission (defined as a CGI-BP-S score ≤2 for 2 months) and treatment with second-generation antipsychotics. The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments.The authors observed no statistically significant advantage of lithium plus OPT on CGI-BP-S scores, necessary clinical adjustments, or proportion with sustained remission. Both groups had similar outcomes across secondary clinical and functional measures. Fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with the OPT-only group (48.3% and 62.5%, respectively).In this pragmatic comparative effectiveness study, a moderate but tolerated dosage of lithium plus OPT conferred no symptomatic advantage when compared with OPT alone, but the lithium-plus-OPT group had less exposure to second-generation antipsychotics. Only about one-quarter of patients in both groups achieved sustained remission of symptoms. These findings highlight the persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment.

Abstract

Late perimenopause and early postmenopause confer an increased risk of depression in the population, yet bipolar disorder mood course during these times remains unclear.Clinic visits in 519 premenopausal, 116 perimenopausal (including 13 women transitioning from perimenopause to postmenopause), and 133 postmenopausal women with bipolar disorder who received naturalistic treatment in the multisite Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study over 19.8 ± 15.5 months were analyzed for mood state. History of postpartum and perimenstrual mood exacerbation and current hormone therapy were evaluated as potential mood predictors.A progression in female reproductive stage (premenopause, perimenopause, and postmenopause) was significantly associated with percent of visits decreasing in euthymia (29.3%, 27.0%, 25.0%, respectively, p < 0.05), decreasing in syndromal mood elevation (5.3%, 4.1%, and 3.0%, respectively, p < 0.001), and increasing in subsyndromal symptoms (47.3%, 50.7%, and 52.7%, respectively, p = 0.05). Thirteen women transitioning from peri- to postmenopause had a significantly greater proportion of visits in syndromal depression (24.4%, p < 0.0005) compared to premenopausal, perimenopausal, and postmenopausal women, while depression in the latter three groups (18.1%, 18.1%, and 19.3%, respectively) did not differ. Perimenstrual and/or postpartum mood exacerbation, or hormone therapy did not significantly alter depression during perimenopause.A progression in female reproductive stages was associated with bipolar illness exacerbation. A small number of women transitioning from perimenopause to postmenopause had significantly greater depression than other female reproductive groups. Euthymia and mood elevation decreased with progressing female reproductive stage. Menstrual cycle or postpartum mood exacerbation, or current hormone therapy use, was not associated with perimenopausal depression. Future studies, which include hormonal assessments, are needed to confirm these preliminary findings.

Abstract

High attrition rates, which occur frequently in longitudinal clinical trials of interventions for bipolar disorder, limit the interpretation of results.The aim of this article is to present design approaches that limited attrition in the Lithium Treatment - Moderate dose Use Study (LiTMUS) for bipolar disorder.LiTMUS was a 6-month randomized, longitudinal multisite comparative effectiveness trial that enrolled bipolar participants who were at least mildly ill. Participants were randomized to either low to moderate doses of lithium or no lithium; other treatments needed for mood stabilization were administered in a guideline-informed, empirically supported, and personalized fashion to participants in both treatment arms.Components of the study design that may have contributed to low attrition (16%) among 283 participants randomized included the use of (1) an intent-to-treat design, (2) a randomized adjunctive single-blind design, (3) participant reimbursement, (4) assessment of intent to attend the next study visit (included a discussion of attendance obstacles when intention was low), (5) quality care with limited participant burden, and (6) target windows for study visits.The relationships between attrition and effectiveness and tolerability of treatment have not been analyzed yet.These components of the LiTMUS design may have limited attrition and may inform the design of future randomized comparative effectiveness trials among similar patients and those from other difficult-to-follow populations.

Abstract

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.

Abstract

Few studies have prospectively examined the relationships of sleep with symptoms and functioning in bipolar disorder.The present study examined concurrent and prospective associations between total sleep time (TST) and sleep variability (SV) with symptom severity and functioning in a cohort of DSM-IV bipolar patients (N = 468) participating in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), all of whom were recovered at study entry.Concurrent associations at study entry indicated that shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity. Mixed-effects regression modeling was used to examine prospective associations in the 196 patients for whom follow-up data were available. Consistent with findings at study entry, shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity over 12 months.These findings highlight the importance of disrupted sleep patterns in the course of bipolar illness.

Strategies for the early recognition of bipolar disorder.journal of clinical psychiatryKetter, T. A.2011; 72 (7)

Abstract

Bipolar disorder often exists for 10 or more years without being correctly diagnosed or treated. Early-onset bipolar disorder is associated with longer treatment delay and a worse outcome than adult-onset bipolar disorder. This activity describes various risk factors for the development of bipolar disorder and discusses possible solutions to the challenges surrounding timely diagnosis.

Abstract

To compare bipolar treatment interventions, using number needed to treat (NNT) and number needed to harm (NNH).Results of randomized controlled clinical trials were used to assess efficacy (NNT for response and relapse/recurrence prevention vs. placebo) and tolerability (e.g. NNH for weight gain and sedation vs. placebo).United States Food and Drug Administration-approved bipolar disorder pharmacotherapies all have single-digit NNTs (i.e. > 10% advantage over placebo), but NNHs for adverse effects that vary widely. Some highly efficacious agents are as likely to yield adverse effects as therapeutic benefit, but may be interventions of choice in more acute severe illness. In contrast, some less efficacious agents with better tolerability may be interventions of choice in more chronic mild-moderate illness.Clinical trials can help inform clinical decision making by quantifying the likelihood of benefit vs. harm. Integrating such data with individual patient circumstances, values, and preferences can help optimize treatment choices.

Abstract

Lamotrigine and quetiapine are commonly used in bipolar disorder, but there are no published systematic studies of their use in combination for treatment-resistant bipolar depression.We studied 39 trials in outpatients (15 with bipolar I disorder, 22 with bipolar II disorder, and 1 with bipolar disorder not otherwise specified; 1 patient had 2 trials) with depression resistant to quetiapine or lamotrigine who were taking a mean of 1.7 other prescription psychotropic medications. Patients were given either open-label lamotrigine or quetiapine naturalistically, for up to 12 weeks of combination therapy.Lamotrigine (mean dose, 204.2 mg/d) plus quetiapine (mean dose, 188.5 mg/d) increased the euthymia rate (0.0% to 46.2%), decreased syndromal (79.5% to 30.8%) and subsyndromal (20.5% to 15.4%) depression rates, and improved Clinical Global Impression-Severity (mean change, -1.0) and Global Assessment of Functioning (mean change, +5.9) scores. Approximately one-fifth of patients discontinued therapy (20.5%) or required subsequent additional pharmacotherapy (20.5%). Only 10.3% discontinued due to adverse effects, and there was no significant change in mean body weight.The findings of this uncontrolled open pilot study must be viewed with caution. However, randomized, double-blind, placebo-controlled studies are warranted to confirm the possibility that combination therapy with lamotrigine and quetiapine is effective and well tolerated in patients with treatment-resistant bipolar depression.

Abstract

Potential predictors of remission in mixed bipolar I disorder were identified using early Clinical Global Impression-Severity (CGI-S) improvement criteria in divalproex-resistant patients randomized to olanzapine augmentation (olanzapine + divalproex; N = 101) in a 6-week, double-blind, placebo-controlled trial. In a post-hoc analysis, receiver operating characteristics of 1-point decreases in the CGI-S total score after 2, 4, 7, and 14 days were examined as predictors of endpoint (Week 6 or last observation) remission of depression and/or mania as defined by 21-item Hamilton Depression Rating Scale (HDRS-21) and Young Mania Rating Scale (YMRS) total score ≤8. Based on a 1-point improvement in CGI-S as a predictor of remission, all odds ratios (ORs) and 95% confidence intervals (CIs) were statistically significant for depression or mania remission criteria. ORs for mixed symptom remission with a decrease ≥1 in CGI-S scores at Day 2 for olanzapine augmentation were (6.727; CI: 2.382, 18.997; p < .001) with negative predictive value = 89.5% and positive predictive value = 44.2%. Changes in HDRS-21 and YMRS individual item scores after 2 days of augmentation as predictors of endpoint remission identified that decreases in HDRS-21 symptom item scores (early, middle, and/or late insomnia; paranoid; agitation; and somatic/gastrointestinal) predicted depressive symptom remission at endpoint, and decreases in YMRS item scores (language-thought disorder and irritability) were associated with manic symptom remission at endpoint. Because remission with augmentation therapy may occur in as few as one in ten individuals who lack very early symptom reduction, lack of early improvement may indicate a need to expediently reassess treatment strategy.

Abstract

Practitioners often combine 2 or more second-generation antipsychotics (SGAs) in patients with bipolar disorder, despite an absence of data to support their safety, tolerability, or efficacy.This study sought to evaluate the safety and tolerability of SGA polytherapy compared to SGA monotherapy in bipolar disorder patients receiving open naturalistic treatment in the 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).A longitudinal cohort of 1,958 patients who were prescribed at least 1 SGA was drawn from 4,035 bipolar patients in STEP-BD recruited between November 1999 and July 2005 and assessed at least quarterly for a mean duration of 21 months. Main outcome measures were the mean quarterly prevalence of adverse events, medical and psychiatric service usage, Global Assessment of Functioning ratings, and percentage of days spent well.Almost 10% of patients taking SGAs were prescribed SGA polytherapy. After controlling for illness onset, age, baseline illness severity, and medication load, patients prescribed SGA polytherapy, compared to monotherapy, exhibited more dry mouth (number needed to harm [NNH] = 4), tremor (NNH = 6), sedation (NNH = 8), sexual dysfunction (NNH = 8), and constipation (NNH = 11) and were almost 3 times as likely to incur more psychiatric and medical care; there was no association with greater global functioning scores or percentage of days spent well.Although SGA polytherapy was fairly common in bipolar disorder, it was associated with increased side effects and health service use but not with improved clinical status or function. Thus, SGA polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.

Abstract

The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder.A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment.The LoLi group (<0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR]=1.96, p=0.042), but not depressive (HR=2.11, p=0.272) episodes, compared to the combined medium (0.6-0.79 mmol/L) and high lithium level (≥0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥0.8 mmol/L) for new manic/mixed (HR=0.96, p=0.893) or depressive (HR=0.95, p=0.922) episodes. The LoOL group (<10mg/day) showed a significantly increased risk of depressive (HR=2.24, p=0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10-20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR=0.94, p=0.895).Lithium levels≥0.6 mmol/L and olanzapine doses≥10mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.

Abstract

At the 2008 annual meeting of the American College of Neuropsychopharmacology (ACNP), a symposium was devoted to the following question: 'what have we learned about the design of pragmatic clinical trials (PCTs) from the recent costly long-term, large-scale trials of psychiatric treatments?' in order to inform the design of future trials. In all, 10 recommendations were generated placing emphasis on (1) appropriate conduct of pragmatic trials; (2) clinical, rather than, merely statistical significance; (3) sampling from the population clinicians are called upon to treat; (4) clinical outcomes of patients, rather than, on outcome measures; (5) use of stratification, controlling, or adjusting when necessary and not otherwise; (6) appropriate consideration of site differences in multisite studies; (7) encouragement of 'post hoc' exploration to generate (not test) hypotheses; (8) precise articulation of the treatment strategy to be tested and use of the corresponding appropriate design; (9) expanded opportunity for training of researchers and reviewers in RCT principles; and (10) greater emphasis on data sharing.

Abstract

Although extensive literature supports connections between bipolar disorder and creativity, possible mechanisms underlying such relationships are only beginning to emerge. Herein we review evidence supporting one such possible mechanism, namely that personality/temperament contribute to enhanced creativity in individuals with bipolar disorder, a theory supported by studies showing that certain personality/temperamental traits are not only common to bipolar disorder patients and creative individuals but also correlate with measures of creativity. Thus, we suggest based on studies using three important personality/temperament measures-the Neuroticism, Extraversion, and Openness Personality Inventory (NEO); the Myers-Briggs Type Indicator (MBTI); and the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A)-that changeable (increased TEMPS-A-cyclothymia) and at times negative (increased NEO-neuroticism) affect and open-minded (increased NEO-openness) and intuitive (increased MBTI-intuition) cognition may contribute importantly to enhanced creativity in individuals with bipolar disorder.

Abstract

To assess quetiapine effectiveness in bipolar disorder (BD) patients in a clinical setting.We naturalistically administered open quetiapine to outpatients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form.96 patients (36 BD I, 50 BD II, 9 BD NOS, 1 Schizoaffective Bipolar Type, mean ± SD age 42.3 ± 13.8 years, 66.7% female) received quetiapine, combined with an average of 2.5 (in 66.7% of patients at least 2) other psychotropic medications and 0.9 non-psychotropic medications, started most often during depressive symptoms (53.1%) or euthymia (37.5%). Mean quetiapine duration and final dose were 385 days and 196 mg/day (50.0% of patients took ?75 mg/day). Quetiapine was discontinued in 38.5% of trials, after on average 307 days, most often (in 19.8%) due to CNS adverse effects (primarily sedation). In 38.5% of trials quetiapine was continued on average 328 days with no subsequent psychotropic added. In 22.9% quetiapine was continued on average 613 days, but had subsequent psychotropic added after on average 113 days, most often for depressive symptoms. In 67 trials started at Stanford, quetiapine tended to primarily maintain euthymia and relieve depressive symptoms. In 29 trials started prior to Stanford, continuing quetiapine tended to primarily maintain euthymia and relieve mood elevation symptoms. Aside from sedation, quetiapine was generally well tolerated.In bipolar disorder outpatients quetiapine had a moderate (38.5%, with 385-day mean duration) discontinuation rate, and commonly did not require subsequent additional pharmacotherapy, suggesting effectiveness in a clinical setting.

Abstract

The spectrum of bipolar disorders includes the subtypes of bipolar I disorder, bipolar II disorder, cyclothymic disorder, and bipolar disorder not otherwise specified (NOS). Because depression is the most pervasive symptom of bipolar disorder, this condition is frequently misdiagnosed as unipolar major depressive disorder. As a result, patients often experience substantive delays in receiving the correct diagnosis and appropriate treatment. To help meet this important diagnostic challenge, various markers have been identified that have predictive value for a bipolar outcome, including early onset of depression, family history of bipolar disorder, atypical depressive symptoms, and the presence of psychosis. Unmet needs in the management of bipolar disorder include an enhanced diagnostic process, more options for treating bipolar depressive episodes, and safer, more tolerable medications for long-term maintenance treatment.

Abstract

To evaluate the efficacy and safety of armodafinil, the longer-lasting isomer of modafinil, when used adjunctively in patients with bipolar depression.In this 8-week, multicenter, randomized, double-blind, placebo-controlled study conducted between June 2007 and December 2008, patients who were experiencing a major depressive episode associated with bipolar I disorder (according to DSM-IV-TR criteria) despite treatment with lithium, olanzapine, or valproic acid were randomly assigned to adjunctive armodafinil 150 mg/d (n = 128) or placebo (n = 129) administered once daily in the morning. The primary outcome measure was change from baseline in the total 30-item Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C??) score. Secondary outcomes included changes from baseline in scores on the Montgomery-Åsberg Depression Rating Scale, among other psychological symptom scales. Statistical analyses were performed using analysis of covariance (ANCOVA), with study drug and concurrent mood stabilizer treatment for bipolar disorder as factors and the corresponding baseline value as a covariate. A prespecified sensitivity analysis was done using analysis of variance (ANOVA) if a statistically significant treatment-by-baseline interaction was found. Tolerability was also assessed.A significant baseline-by-treatment interaction in the total IDS-C?? score (P = .08) was found. Patients administered adjunctive armodafinil showed greater improvement in depressive symptoms as seen in the greater mean ± SD change on the total IDS-C?? score (-15.8 ± 11.57) compared with the placebo group (-12.8 ± 12.54) (ANOVA: P = .044; ANCOVA: P = .074). No differences between treatment groups were observed in secondary outcomes. Adverse events reported more frequently in patients receiving adjunctive armodafinil were headache, diarrhea, and insomnia. Armodafinil was not associated with an increased incidence and/or severity of suicidality, depression, or mania or with changes in metabolic profile measurements.In this proof-of-concept study, adjunctive armodafinil 150 mg/d appeared to improve depressive symptoms according to some, but not all, measures and was generally well tolerated in patients with bipolar depression.clinicaltrials.gov Identifier: NCT00481195.

Abstract

Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD.Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women.As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight-liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity.Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed.

Abstract

Divalproex extended-release (divalproex-ER) is effective in acute mania, and limited data suggest divalproex may have efficacy in acute bipolar depression.A 7-week, open-label trial of divalproex-ER monotherapy or adjunctive therapy was conducted in 28 outpatients (15 female, mean age 36.7+/-9.1, and mean duration of illness 22.1+/-11.1 years) with bipolar II depression (39% with rapid cycling course of illness within the prior year). Divalproex-ER was generally given as a single dose at bedtime, starting at 250mg and increased by 250mg every 4 days to symptom relief or adverse effects. Efficacy was assessed using weekly prospective Montgomery Asberg Depression Rating Scale (MADRS) scores.Overall, mean divalproex-ER final doses and serum concentrations were 1469mg/day and 80.1microg/mL, respectively. Mean MADRS scores (last observation carried forward) decreased significantly from baseline in patients in the overall group (from 30.1 to 15.2, p

Abstract

Bipolar disorder shares depressive symptoms with unipolar major depressive disorder but is defined by episodes of mania or hypomania. Bipolar disorder in its broadest sense has a community lifetime prevalence of 4% and is a severely impairing illness that impacts several aspects of patients' lives. Race, ethnicity, and gender have no effect on prevalence rates, but women are more likely to experience rapid cycling, mixed states, depressive episodes, and bipolar II disorder than men. Patients with bipolar disorder have high rates of disability and higher rates of mortality than individuals without bipolar disorder. Natural causes such as cardiovascular disease and diabetes, as well as suicide and other "unnatural" causes are key contributors to the high mortality rate. The costs associated with bipolar disorder include not only the direct costs of treatment, but also the much greater indirect costs of decreased productivity, excess unemployment, and excess mortality.

Abstract

Findings from previous research on the neural substrates of mania have been variable, in part because of heterogeneity of techniques and patients. Though some findings have been replicated, the constellation of neurophysiological changes has not been demonstrated simultaneously. We sought to determine resting state cerebral metabolic changes associated with relatively severe acute mania. Resting positron emission tomography with (18)fluorodeoxyglucose was performed in bipolar disorder patients with severe mania and in healthy controls. Statistical parametric mapping was used to determine regions of differential metabolism. Relative to controls, bipolar disorder patients with mania exhibited significantly decreased cerebral metabolism in both the dorsolateral prefrontal regions and the precuneus. Conversely, manic patients exhibited significant hypermetabolism in the parahippocampal complex, temporal lobe, anterior cingulate, and subgenual prefrontal cortex compared with controls. These results demonstrate simultaneous resting limbic/paralimbic hypermetabolism and prefrontal hypometabolism during mania. The findings support the hypothesis of corticolimbic dysregulation as a crucial contributor to the pathophysiology of bipolar disorder.

Abstract

Practical strategies are available for primary care physicians to monitor psychiatric and medical outcomes as well as treatment adherence in patients with bipolar disorder. Current depressive symptoms can be assessed with tools like the 9-item Patient Health Questionnaire or Beck Depression Inventory. Lifetime presence or absence of manic or hypomanic symptoms can be assessed using the Mood Disorder Questionnaire (MDQ). These measures can be completed quickly by patients prior to appointments. Sensitivity of such ratings, particularly the MDQ, can be increased by having a significant other also rate the patient. Clinicians should also screen mood disorder patients for psychiatric comorbidities that are common in this population such as anxiety and substance use disorders. While patients with bipolar disorder may commonly be nonadherent with prescribed medication regimens, strategies that can help include having frank discussions with the patient, selecting medication collaboratively, adding psychotherapy with a psychoeducation element, monitoring appointment-keeping, using patient self-reports of medication-taking, enlisting the aid of significant others, and measuring plasma drug levels. Medical monitoring is needed to assess the safety and tolerability of psychotropic medications. All of the approved medications for bipolar disorder have at least 1 boxed warning for serious side effects, but are also associated with other common management-limiting side effects such as sedation, tremor, unsteadiness, restlessness, nausea, vomiting, diarrhea, constipation, weight gain, and metabolic problems. Routine monitoring is particularly needed for obesity, metabolic syndrome, and cardiovascular disorders, which lead to high rates of medical morbidity and mortality in patients with bipolar disorder. Monitoring protocols such as the one recommended by the American Diabetes Association for patients taking second-generation antipsychotics can be used for regular assessment.

Abstract

We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.

Abstract

The diagnosis of bipolar disorder (BD) in children is increasing, and often requires a comprehensive treatment plan to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for the treatment and stabilization of disrupted mood. Current evidence collectively demonstrates, by randomized controlled design, that atypical antipsychotics have efficacy for the treatment of acute manic or mixed symptoms in children and adolescents with BD. Additional longitudinal and biological studies are warranted to characterize the effects of atypical antipsychotics on all phases and stages of bipolar illness development in children and adolescents.

Abstract

Recent data indicate that lithium use for bipolar disorder has declined over the last decade and that lithium largely has been replaced with alternate, commercially promoted medications that may or may not result in better outcomes.This article describes the rationale and study design of LiTMUS, a multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. LiTMUS seeks to address whether initiating therapy at lower doses of lithium as part of optimized treatment (OPT, guideline-informed, evidence-based, and personalized pharmacotherapy) improves outcomes and decreases the need for other medication changes across 6 months of therapy.LiTMUS will randomize 284 adults with bipolar disorder (Type I or II) across 6 study sites. The co-primary outcomes are overall illness severity on clinical global improvement scale for bipolar disorder and a novel measure, necessary clinical adjustments. This metric provides a composite that reflects both clinical response and tolerability. Other relevant outcomes include full symptomatic recovery, quality of life, suicidal behaviors, and moderators of suicidality.As of August 28th, 2009, we have consented 338 patients and randomized 281 for this study.The potential limitations of the study include an arbitrary definition of 'low, but effective' doses of lithium, lack of a placebo-controlled group, open treatment, and use of a new outcome measure (i.e., necessary clinical adjustments).We expect that this study will inform our understanding of the effectiveness of low to moderate doses of lithium therapy for individuals with bipolar disorder.

Abstract

Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS).Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL.Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.

Abstract

During post-acute phase pharmacotherapy for bipolar disorder, there has been little empirical study to establish when emerging mania symptoms (1) are of clinical significance and (2) reflect iatrogenic events versus the natural course of illness.Secondary analyses were conducted in a previously studied group of bipolar I disorder (DSM-IV) outpatients randomly assigned to lamotrigine monotherapy (n=171) or placebo (n=121), and a larger prerandomization group (N=966) during open-label titration of lamotrigine, following an index depressive episode. Time until the emergence of mania symptoms, at varying severity thresholds, was examined over 6 months for lamotrigine versus placebo, while controlling for potential confounding factors in Cox proportional hazard models. Subject enrollment occurred between July 1997 and August 2001.Rates of mood elevation during both acute open-label and randomized continuation phases of lamotrigine treatment were comparable to those seen with placebo during the randomized phase. The hazard ratio for the emergence of mania symptoms with lamotrigine was not significantly different from placebo (hazard ratio=0.79; 95% CI, 0.53 to 1.16), with an upper bound that suggests no meaningful increase in susceptibility toward mania with lamotrigine. By contrast, clinically meaningful rises in mania symptom severity were predicted by baseline residual manic symptoms prerandomization and by the number of manic, hypomanic, or mixed episodes in the past year.Based on a composite definition of mood destabilization involving a range of severity thresholds for emerging signs of mania, lamotrigine confers no meaningful elevated risk relative to placebo for mood destabilization in bipolar I disorder. Rather, illness burden related to residual or lifetime mania features may hold greater importance for explaining mania relapses or breakthrough manic features during lamotrigine continuation pharmacotherapy.

Abstract

To assess the relationship between depressive relapse and change in thyroid function in an exploratory post hoc analysis from a controlled maintenance evaluation of bipolar I disorder.Mean thyroid-stimulating hormone (TSH) and outcome data were pooled from two 18-month, double-blind, placebo-controlled, maintenance studies of lamotrigine and lithium monotherapy. A post hoc analysis of 109 subjects (n = 55 lamotrigine, n = 32 lithium, n = 22 placebo) with serum TSH values at screening and either week 52 (+/-14 days) or study drop-out was conducted.Lithium-treated subjects who required an intervention for a depressive episode had a significantly higher adjusted mean TSH level (4.4 microIU/ml) compared with lithium-treated subjects who did not require intervention for a depressive episode (2.4 microIU/ml).Lithium-related changes in thyroid function are clinically relevant and should be carefully monitored in the maintenance phase of bipolar disorder to maximize mood stability and minimize the risk of subsyndromal or syndromal depressive relapse.

Abstract

Mood states are associated with alterations in cerebral blood flow and metabolism, yet changes in cerebral structure are typically viewed in the context of enduring traits, genetic predispositions, or the outcome of chronic psychiatric illness. Magnetic resonance imaging (MRI) scans were obtained from two groups of patients with bipolar disorder. In one group, patients met criteria for a current major depressive episode whereas in the other no patient did. No patient in either group met criteria for a current manic, hypomanic, or mixed episode. Groups were matched with respect to age and illness severity. Analyses of gray matter density were performed with Statistical Parametric Mapping software (SPM5). Compared with non-depressed bipolar subjects, depressed bipolar subjects exhibited lower gray matter density in the right dorsolateral and bilateral dorsomedial prefrontal cortices and portions of the left parietal lobe. In addition, gray matter density was greater in the left temporal lobe and right posterior cingulate cortex/parahippocampal gyrus in depressed than in non-depressed subjects. Our findings highlight the importance of mood state in structural studies of the brain-an issue that has received insufficient attention to date. Moreover, our observed differences in gray matter density overlap metabolic areas of change and thus have implications for the conceptualization and treatment of affective disorders.

Abstract

Emerging data suggest the menopausal transition may be a time of increased risk for depression. This study examines the course of bipolar disorder focusing on depressive symptoms in menopausal transition age women, compared to similar-aged men as well as younger adult women and men.Outpatients with bipolar disorder were assessed with the systematic treatment enhancement program for bipolar disorder (STEP-BD) affective disorders evaluation and longitudinally monitored during naturalistic treatment with the STEP-BD clinical monitoring form. Clinical status (syndromal/subsyndromal depressive symptoms, syndromal/subsyndromal elevation or mixed symptoms, and euthymia) was compared between menopausal transition age women (n=47) and pooled similar-aged men (n=30) 45-55 years old, younger women (n=48) and men (n=39) 30-40 years old.Subjects included 164 bipolar disorder patients (67 type I, 82 type II, and 15 not otherwise specified), 34% were rapid cycling and 58% women. Bipolar II disorder/bipolar NOS was more common in women. Monitoring averaged 30+/-22 months, with an average of 0.9+/-0.5 clinic visits/month. Menopausal age women had a significantly greater proportion of visits with depressive symptoms (p<0.05), significantly fewer euthymic visits (p<0.05) and no difference in proportion of visits with elevated/mixed symptoms compared to pooled comparison group.Menopausal transition age women with bipolar disorder experience a greater proportion of clinic visits with depressive symptoms compared to similarly aged men, and younger women and men with bipolar disorder. Further systematic assessment on the influence of the menopausal transition and reproductive hormones upon mood is needed to better inform clinical practice in treating women with bipolar disorder.

Abstract

Sleep disturbance in bipolar disorder can be both a risk factor and symptom of mood episodes. However, the associations among sleep and clinical characteristics, function, and quality of life in bipolar disorder have not been fully investigated.The prevalence of sleep disturbance, duration, and variability, as well as their associations with mood, function, and quality of life, was determined from 2024 bipolar patients enrolled in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).Analyses indicated that 32% of patients were classified as short sleepers, 38% normal sleepers, and 23% long sleepers. Overall, short sleepers demonstrated greater mood elevation, earlier age at onset, and longer illness duration compared to both normal and long sleepers. Both short and long sleepers had greater depressive symptoms, poorer life functioning, and quality of life compared to normal sleepers.Short sleep duration in bipolar disorder was associated with a more severe symptom presentation, whereas both short and long sleep duration are associated with poorer function and quality of life compared to normal sleep duration. Sleep disturbance could be a trait marker of bipolar disorder, though longitudinal assessments are warranted to assess potential causal relations and the longer-term implications of sleep disturbance in bipolar disorder.

Abstract

Many patients with bipolar disorder receive multi-drug treatment regimens, but the distinguishing profiles of patients who receive complex pharmacologies have not been established.Prescribing patterns of lithium, anticonvulsants, antidepressants, and antipsychotics were examined for 4,035 subjects with bipolar disorder (DSM-IV) immediately prior to entering the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Subjects were recruited for participation across 22 centers in the United States between November 1999 and July 2005. The quality receiver operating characteristic (ROC) method was used to develop composite profiles of patients receiving complex regimens (p < .01 for all iterations).Use of 3 or more medications occurred in 40% of subjects, while 18% received 4 or more agents. Quality ROC analyses revealed that subjects had a 64% risk for receiving a complex regimen (> or = 4 medications) if they had (1) ever taken an atypical antipsychotic, (2) > or = 6 lifetime depressive episodes, (3) attempted suicide, and (4) an annual income > or = $75,000. Complex polypharmacy was least often associated with lithium, divalproex, or carbamazepine and most often associated with atypical antipsychotics or antidepressants. Contrary to expectations, a history of psychosis, age at onset, bipolar I versus II subtype, history of rapid cycling, prior hospitalizations, current illness state, and history of alcohol or substance use disorders did not significantly alter the risk profiles for receiving complex regimens.Complex polypharmacy involving at least 4 medications occurs in approximately 1 in 5 individuals with bipolar disorder. Use of traditional mood stabilizers is associated with fewer cotherapies. Complex regimens are especially common in patients with substantial depressive illness burden and suicidality, for whom simpler drug regimens may fail to produce acceptable levels of response.clinicaltrials.gov Identifier: NCT00012558.

Abstract

The corticolimbic dysregulation hypothesis of bipolar disorder suggests that depressive symptoms are related to dysregulation of components of an anterior paralimbic network (anterior cingulate, anterior temporal cortex, dorsolateral prefrontal cortex, parahippocampal gyrus, and amygdala) with excessive anterior limbic activity accompanied by diminished prefrontal activity. In younger patients, such abnormalities tend to resolve with remission of depression, but it remains to be established whether the same is true for older patients. This was a cross-sectional, between-subjects design conducted with 16 euthymic, medicated patients with bipolar disorder (10 type I, six type II) and 11 age-matched healthy controls. All participants were over age 50. Our main outcome measures were relative rates of cerebral metabolism derived from a resting (18)flourodeoxyglucose positron emission tomography scan in specified regions of interest in the corticolimbic network. Resting metabolic rates in bipolar patients were significantly greater than in controls in bilateral amygdalae, bilateral parahippocampal gyri, and right anterior temporal cortex (BA 20, 38); they were significantly lower in bipolar patients than in controls in the bilateral dorsolateral prefrontal cortices (BA 9, 10, 46). The evidence of corticolimbic dysregulation observed is consistent with the hypothesis that bipolar disorder entails progressive, pernicious neurobiological disruptions that may eventually persist during euthymia. Persistent corticolimbic dysregulation may be related to residual affective, behavioral, and cognitive symptoms in older patients with bipolar disorder, even when not experiencing syndromal mood disturbance.

Abstract

Combination treatments for patients with bipolar disorder can be potentially advantageous for patients due to the therapeutic synergy. However, combining treatments can also increase the possibility of drug interactions and adverse effects. When considering using combination therapy, clinicians should evaluate the efficacy, tolerability, and safety of the combination for each individual patient. Physicians should exercise caution when treating patients with a combination of medications and strive to use monotherapy when feasible.

Abstract

This study explored whether cerebral metabolic changes seen in treatment resistant and rapid cycling bipolar depression inpatients are also found in an outpatient sample not specifically selected for treatment resistance or rapid cycling. We assessed 15 depressed outpatients with bipolar disorder (six type I and nine type II) who were medication-free for at least 2 weeks and were not predominantly rapid cycling. The average 28-item Hamilton Depression Scale (HAM-D) total score was 33.9. The healthy control group comprised 19 age-matched subjects. All participants received a resting quantitative 18F-fluoro-deoxyglucose positron emission tomography scan. Data analyses were performed with Statistical Parametric Mapping (SPM5). Analyses revealed that depressed patients exhibited similar global metabolism, but decreased absolute regional metabolism in the left much more than right dorsolateral prefrontal cortex, bilateral (left greater than right) insula, bilateral subgenual prefrontal cortex, anterior cingulate, medial prefrontal cortex, ventral striatum, and right precuneus. No region exhibited absolute hypermetabolism. Moreover, HAM-D scores inversely correlated with absolute global metabolism and regional metabolism in the bilateral medial prefrontal gyrus, postcentral gyrus, and middle temporal gyrus. Analysis of relative cerebral metabolism yielded a similar, but less robust pattern of findings. Our findings confirm prefrontal and anterior paralimbic metabolic decreases in cerebral metabolism outside of inpatients specifically selected for treatment resistant and rapid cycling bipolar disorder. Prefrontal metabolic rates were inversely related to severity of depression. There was no evidence of regional hypermetabolism, perhaps because this phenomenon is less robust or more variable than prefrontal hypometabolism.

Abstract

Patients experiencing breakthrough manic or mixed episodes during maintenance therapy for bipolar disorder should first be assessed to ensure they are receiving an optimal dose of the first-line medication. If further intervention is needed, one option is to combine an atypical antipsychotic and a mood stabilizer. The decision to use a particular combination should be made on the basis of the efficacy, tolerability, and safety of each medication for individual patients. Psychosocial therapy as an adjunct to medication is also useful in delaying relapse.

Abstract

To assess lamotrigine effectiveness in bipolar disorder (BD) patients in a clinical setting.Open lamotrigine was naturalistically administered to outpatients at the Stanford University BD Clinic assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form.One hundred and ninety-seven patients (64 BD I, 110 BD II, 21 BD NOS, 2 Schizoaffective Bipolar Type, mean+/-SD age 42.2+/-14.4 years, 62% female) had 200 trials of lamotrigine. Lamotrigine was combined with a mean of 2.1+/-1.5 other psychotropic medications, most often during euthymia or depressive symptoms. Mean lamotrigine duration was 434+/-444 days, and mean final dose was 236+/-132mg/day without valproate, and 169+/-137mg/day with valproate. Lamotrigine was discontinued in only 26.5% of trials at 255+/-242 days, most often due to inefficacy, and seldom due to adverse effects. In 31.5% of trials lamotrigine was continued 264+/-375 days with no subsequent psychotropic added. In 42.0% of trials lamotrigine was continued 674+/-479 days, but had subsequent psychotropic added at 146+/-150 days, most often for anxiety/insomnia and depressive symptoms. In 145 trials started at Stanford, lamotrigine primarily yielded relief of depressive symptoms or maintained euthymia. In 55 trials in which lamotrigine was started prior to Stanford, lamotrigine primarily maintained euthymia. Lamotrigine was generally well tolerated, with no serious rash, and only 3.5% discontinuing due to benign rash.In a cohort of bipolar disorder outpatients commonly with comorbid conditions, and most often receiving complex combination therapy, lamotrigine had a low (26.5%, with an overall mean duration of treatment of 434 days) discontinuation rate, suggesting effectiveness in BD in a clinical setting.

Abstract

Unipolar and bipolar disorders have often been reported to exhibit abnormal regional brain activity in prefrontal cortex and paralimbic structures compared with healthy controls. We sought to ascertain how regions postulated to be abnormal in bipolar and unipolar disorders were functionally connected to the rest of the brain, and how this associativity differed from healthy controls. Thirty patients with bipolar disorder (BPs), 34 patients with unipolar disorder (UPs), and 66 healthy volunteers (Willis, M.W., Benson, B.E., Ketter, T.A., Kimbrell, T.A., George, M.S., Speer, A.M., Herscovitch, P., Post, R.M., 2008. Interregional cerebral metabolic associativity during a continuous performance task in healthy adults. Psychiatry Research: Neuroimaging 164 (1)) were imaged using F-18-fluorodeoxyglucose and positron emission tomography (FDG-PET) while performing an auditory continuous performance task (CPT). Five bilateral regions of interest (ROIs), namely dorsolateral prefrontal cortex (DLPFC), insula, inferior parietal cortex (INFP), thalamus and cerebellum, were correlated with normalized cerebral metabolism in the rest of the brain while covarying out Hamilton Depression Rating Scale Scores. In bipolar patients compared with controls, metabolism in the left DLPFC and INFP, and bilateral thalamus and insula had more positive and fewer negative metabolic correlations with other brain regions. In contrast, compared with controls, unipolar patients had fewer significant correlative relationships, either positive or negative. In common, bipolar and unipolar patients lacked the normal inverse relationships between the DLPFC and cerebellum, as well as relationships between the primary ROIs and other limbic regions (medial prefrontal cortex, anterior cingulate, and temporal lobes) compared with controls. Associations of DLPFC and INFP with other brain areas were different in each hemisphere in patients and controls. Bipolar patients exhibited exaggerated positive coherence of activity throughout the brain, while unipolar patients showed a paucity of normal interrelationships compared with controls. These abnormal patterns of metabolic associativity suggest marked interregional neuronal dysregulation in bipolar and unipolar illness exists beyond that of mere absolute regional differences from control levels, and provides rationale for using acute and long-term therapies that may re-establish and maintain normal associativity in these devastating illnesses.

Abstract

One emerging hypothesis regarding psychiatric illnesses is that they arise from the dysregulation of normal circuits or neuroanatomical patterns. In order to study mood disorders within this framework, we explored normal metabolic associativity patterns in healthy volunteers as a prelude to examining the same relationships in affectively ill patients (Part II). We applied correlational analyses to regional brain activity as measured with FDG-PET during an auditory continuous performance task (CPT) in 66 healthy volunteers. This simple attention task controlled for brain activity that otherwise might vary amongst affective and cognitive states. There were highly significant positive correlations between homologous regions in the two hemispheres in thalamic, extrapyramidal, orbital frontal, medial temporal and cerebellar areas. Dorsal frontal, lateral temporal, cingulate, and especially insula, and inferior parietal areas showed less significant homologous associativity, suggesting more specific lateralized function. The medulla and bilateral thalami exhibited the most diverse interregional associations. A general pattern emerged of cortical regions covarying inversely with subcortical structures, particularly the frontal cortex with cerebellum, amygdala and thalamus. These analytical data may help to confirm known functional and neuroanatomical relationships, elucidate others as yet unreported, and serve as a basis for comparison to patients with psychiatric illness.

Abstract

To investigate differences in prevalence of mood elevation, distress and depression among first-year undergraduates at Oxford and Stanford universities.An online survey was sent to Oxford and Stanford first-year undergraduate students for two consecutive years in the winter of 2005 and 2006. Students completed a survey that assessed mood symptoms and medication use.Both universities had similar rates of distress by General Health Questionnaire (Oxford - 42.4%; Stanford - 38.3%), depression by Primary Care Evaluation of Mental Disorders (Oxford - 6.2%; Stanford - 6.6%), and psychotropic and non-psychotropic medication usage (psychotropic: Oxford - 1.5%; Stanford 3.5%; nonpsychotropic: Oxford - 13.3%; Stanford - 18%). Oxford had higher rates of mood elevation by Mood Disorder Questionnaire (MDQ) (Oxford - 4%; Stanford - 1.7%).Oxford and Stanford students have similar rates of mood distress, depression and general medication usage. Students at Oxford have a higher prevalence of MDQ scores that possibly indicate a bipolar disorder, while Stanford students are prescribed more psychotropics.

Abstract

Evidence-based medicine integrates data from clinical trials into clinical care while efficacy studies assess simplified interventions in simplified populations. The findings of such studies are useful in obtaining Food and Drug Administration approval of medications but often fail to generalize to the more complex populations and interventions commonly seen in clinical practice. Recently, an increased emphasis has been placed on effectiveness studies (also referred to as pragmatic or practical studies) designed to yield findings that can be generalized to the clinical management of patients with bipolar disorder. Mood stabilizers and increasingly second-generation antipsychotics are considered the foundation of treatment for bipolar disorder. In contrast, adjunctive antidepressants should be avoided when patients present with manic and mixed episodes. Additional interventions--such as psychoeducation and care coordination--when combined with pharmacotherapy, can lessen the frequency and severity of mood episodes, especially mania. These interventions, combined with judicious pharmacotherapy, can help minimize the impact of adverse effects and related nonadherence so that patients can achieve affective stability, regain psychosocial function, and maintain health.

Abstract

To identify caregivers at risk for adverse health effects associated with caregiving, the stress, coping, health and service use of 500 primary caregivers of patients with bipolar disorder were assessed at baseline, 6, and 12 months. K-means cluster analysis and ANOVA identified and characterized groups with differing baseline stress/coping profiles. Mixed effects models examined the effects of cluster, time, and covariates on health outcomes. Three groups were identified. Burdened caregivers had higher burden and avoidance coping levels, and lower mastery and social support than effective and stigmatized caregivers; stigmatized caregivers reported the highest perceived stigma (p < 0.05). Effective and stigmatized groups had better health outcomes and less service use than the burdened group over time; stigmatized caregivers had poorer self-care than effective caregivers. Cluster analysis is a promising method for identifying subgroups of caregivers with different stress and coping profiles associated with different health-related outcomes.

Abstract

Data are emerging in bipolar disorder regarding mood across phases of the female reproductive life, yet information about mood during the menopausal transition remains limited. The menopausal transition in women without mood disorders is associated with an increase in depression. This study assesses mood course during the menopausal transition in women with bipolar disorder.We monitored mood episodes in 47 women with bipolar disorder ages 45-55 for 17.0+/-14.0 months with systematic treatment enhancement program for bipolar disorder (STEP-BD) standardized evaluations. Charts were additionally reviewed for menstrual status and menstrual history, as well as mood episode type, duration, frequency and history.During the menopausal transition 68% of women with bipolar disorder experienced at least one depressive episode. Depression (but not mood elevation) episode frequency significantly increased during the menopausal transition compared to reported frequency during patients' reproductive years. History of pre-menstrual and or post-partum mood instability did not predict perimenopausal mood episodes.Women with bipolar disorder experience a high frequency of depressive episodes during perimenopausal years and this frequency appears greater than during prior reproductive years. Prospective controlled studies are needed to better understand the course of mood episodes and to enhance the effectiveness of managing bipolar disorder during the menopausal transition.

Abstract

As patients with mood disorders manifest heterogeneity in phenomenology, pathophysiology, etiology, and treatment response, a biological classification of mental disease is urgently needed to advance research. Patient and methodological variability complicates the comparison of neuroimaging study results and limits heuristic model development and a biologically-based diagnostic schema.We have critically reviewed and compared the magnetic resonance neuroimaging literature to determine the degree and directionality of volumetric changes in brain regions putatively implicated in the pathophysiology of major depressive disorder (MDD) versus bipolar disorder (BD).A total of 140 published magnetic resonance imaging investigations evaluating subjects with BD or MDD were selected to provide a summary and interpretation of volumetric neuroimaging results in MDD and BD. Further commentary on the pathophysiological implications, and putative cellular and pharmacological mechanisms, is also provided.While whole brain volumes of patients with mood disorders do not differ from those of healthy controls, regional deficits in the frontal lobe, particularly in the anterior cingulate and the orbitofrontal cortex, appear to consistently differentiate subjects with mood disorders from the general population. Preliminary findings also suggest that subcortical structures, particularly the striatum, amygdala, and hippocampus, may be differentially affected in MDD and BD.Structural neuroimaging studies have consistently identified regional abnormalities in subjects with mood disorders. Future studies should strive to definitively establish the influence of age and medication.

Abstract

The American Psychiatric Association guidelines for treating bipolar disorder recommend combination therapies to treat patients experiencing severe acute manic or mixed episodes and breakthrough manic or mixed episodes during maintenance therapy. Combination therapies approved by the U.S. Food and Drug Administration for the treatment of acute manic states include the use of second-generation antipsychotics, such as olanzapine, risperidone, quetiapine, and aripiprazole in combination with lithium or divalproex; for the treatment of acute bipolar depression, the olanzapine plus fluoxetine combination; and for maintenance treatment, quetiapine combined with lithium or valproate. When combining medications for the management of patients with bipolar disorders, physicians face a potentially complex treatment strategy. Available agents have different mechanisms of action, routes of metabolism and excretion, therapeutic effects, and side effects. Combining treatments can be advantageous owing to therapeutic synergy; however, the liability is an increased possibility of adverse effects. The decision to use a combination therapy should be made on the basis of the efficacy, tolerability, and safety of each medication and their specific combination for individual patients.

Abstract

Fluctuations in mood are quintessential features of bipolar disorder; however, previous studies have seldom examined the extent to which pharmacotherapies for bipolar disorder may reduce or ameliorate daily or weekly mood variability. The anticonvulsant lamotrigine has demonstrated efficacy for relapse prevention in bipolar disorder, but its possible mood-stabilizing properties on a day-to-day or week-to-week basis have not previously been investigated.Weekly mood shifts were examined over 26 weeks using patients' self-reported prospective Life Chart Method (LCM) data obtained as part of a previously reported randomized relapse prevention comparison of lamotrigine monotherapy or placebo in 182 bipolar patients with DSM-IV rapid cycling. Generalized estimating equation (GEE) analyses were used to compare treatment arms for subjects who achieved euthymia across weeks.After adjusting for potential confounding factors, a final GEE model revealed that subjects taking lamotrigine were 1.8 times more likely than those taking placebo to achieve euthymia, as measured by LCM, at least once per week over 6 months (95% confidence interval [CI] = 1.03-3.13). Subjects taking lamotrigine had an increase of .69 more days per week euthymic as compared with those taking placebo (p = .014).Achievement of euthymia across weeks represents a novel paradigm shift in gauging the mood-stabilizing properties of a psychotropic agent. The present findings demonstrate the utility of the prospective Life Chart Method for assessing longitudinal mood stability during randomized clinical trials for bipolar disorder. The results lend support to the potential mood-stabilizing properties of lamotrigine monotherapy for bipolar disorder.

Abstract

Associations between eminent creativity and bipolar disorders have been reported, but there are few data relating non-eminent creativity to bipolar disorders in clinical samples. We assessed non-eminent creativity in euthymic bipolar (BP) and unipolar major depressive disorder (MDD) patients, creative discipline controls (CC), and healthy controls (HC).49 BP, 25 MDD, 32 CC, and 47 HC (all euthymic) completed four creativity measures yielding six parameters: the Barron-Welsh Art Scale (BWAS-Total, and two subscales, BWAS-Dislike and BWAS-Like), the Adjective Check List Creative Personality Scale (ACL-CPS), and the Torrance Tests of Creative Thinking--Figural (TTCT-F) and Verbal (TTCT-V) versions. Mean scores on these instruments were compared across groups.BP and CC (but not MDD) compared to HC scored significantly higher on BWAS-Total (45% and 48% higher, respectively) and BWAS-Dislike (90% and 88% higher, respectively), but not on BWAS-Like. CC compared to MDD scored significantly higher (12% higher) on TTCT-F. For all other comparisons, creativity scores did not differ significantly between groups.We found BP and CC (but not MDD) had similarly enhanced creativity on the BWAS-Total (driven by an increase on the BWAS-Dislike) compared to HC. Further studies are needed to determine the mechanisms of enhanced creativity and how it relates to clinical (e.g. temperament, mood, and medication status) and preclinical (e.g. visual and affective processing substrates) parameters.

Abstract

To determine the neural responses invoked in the recognition of facial fear and disgust in euthymic bipolar patients as compared with healthy subjects.This study examined 10 female euthymic bipolar patients, and 10 suitably matched healthy subjects using functional magnetic resonance imaging (fMRI) while subjects were engaged in an explicit facial emotion recognition task involving fear, disgust and neutral expressions. The activation paradigm involved nominating the facial expression using specified response keys. Behavioural data were collected and analysed and both within-group (Fear versus Neutral; Disgust versus Neutral) and random-effects between-group analyses were performed on fMRI data using BrainVoyager (Brain Innovations, Maastricht, the Netherlands).Patients were equally accurate in identifying facial expressions as healthy subjects but were slower to respond, especially with respect to fear and disgust. Responses to fear and disgust (within-group analyses) resulted in activation of anticipated brain regions such as amygdala and insula, respectively. However, between-group random effects analysis revealed differential responses to both disgust and fear in both healthy subjects and euthymic bipolar patients such that euthymic bipolar patients responded largely to fear and healthy subjects responded more so to disgust. This partitioning of responsiveness was reflected by differential activation involving the hippocampus and amygdala.Greater responsiveness to fear with hippocampal activation in patients perhaps reflects recollection of traumatic events associated with past experiences of illness or simply the use of a more mnemonic (hippocampal) as opposed to affective (amygdala) approach when performing the task. It is possible that in bipolar disorder, prefrontal-subcortical network dysfunction that relegates neural processing to limbic regions is impaired and that clinically euthymic bipolar patients, although able to accurately and effectively identify emotions such as fear and disgust, are limited in their ability to interpret their salience. The implications of these findings are discussed.

Abstract

To investigate temperament-creativity relationships in euthymic bipolar (BP) and unipolar major depressive (MDD) patients, creative discipline controls (CC), and healthy controls (HC).49 BP, 25 MDD, 32 CC, and 47 HC (all euthymic) completed three self-report temperament/personality measures: the Revised NEO Personality Inventory (NEO-PI-R), the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A), and the Temperament and Character Inventory (TCI); and four creativity measures yielding six parameters: the Barron-Welsh Art Scale (BWAS-Total, BWAS-Like, and BWAS-Dislike), the Adjective Check List Creative Personality Scale (ACL-CPS), and the Torrance Tests of Creative Thinking--Figural (TTCT-F) and Verbal (TTCT-V) versions. Factor analysis was used to consolidate the 16 subscales from the three temperament/personality measures, and the resulting factors were assessed in relationship to the creativity parameters.Five personality/temperament factors emerged. Two of these factors had prominent relationships with creativity measures. A Neuroticism/Cyclothymia/Dysthymia Factor, comprised mostly of NEO-PI-R-Neuroticism and TEMPS-A-Cyclothymia and TEMPS-A-Dysthymia, was related to BWAS-Total scores (r=0.36, p<0.0001) and BWAS-Dislike subscale scores (r=0.39, p<0.0001). An Openness Factor, comprised mostly of NEO-PI-R-Openness, was related to BWAS-Like subscale scores (r=0.28, p=0.0006), and to ACL-CPS scores (r=0.46, p<0.0001). No significant relationship was found between temperament/personality and TTCT-F and TTCT-V scores.Neuroticism/Cyclothymia/Dysthymia and Openness appear to have differential relationships with creativity. The former could provide affective (Neuroticism, i.e. access to negative affect, and Cyclothymia, i.e. changeability of affect) and the latter cognitive (flexibility) advantages to enhance creativity. Further studies are indicated to clarify mechanisms of creativity and its relationships to affective processes and bipolar disorders.

Abstract

Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania.In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined.Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups.The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

Abstract

The objectives of this analysis are to elucidate the clinical significance of antidepressant effects with quetiapine by evaluating number needed to treat as well as time to response and remission with quetiapine monotherapy in patients with acute bipolar depression. A post-hoc analysis was conducted of 542 patients with bipolar I or II disorder, (moderate to severe depression), randomized to 8 weeks of double-blind treatment with quetiapine 600 mg/day (n=180), quetiapine 300 mg/day (n=181), or placebo (n=181). Number needed to treat, time to response (> or =50% reduction from baseline in Montgomery-Asberg Depression Rating Scale total score) and time to remission (Montgomery-Asberg Depression Rating Scale total score < or =12) were evaluated. Response rates at week 8 were 58.2 and 57.6% for quetiapine 600 and 300 mg/day, respectively, and 36.1% for placebo (P<0.001). Remission rates were 52.9% for both quetiapine groups and 28.4% for placebo (P<0.001). The number needed to treat was five for both response and remission for quetiapine (600 and 300 mg/day) compared with placebo. Median time to response and remission were significantly shorter with quetiapine 600 and 300 mg/day than placebo. No between-group difference was found in the incidence of treatment-emergent mania or hypomania (quetiapine 600 mg/day: 2.2%, quetiapine 300 mg/day: 3.9, and placebo: 3.9%). In conclusion, quetiapine compared with placebo significantly reduces time to response and remission compared with placebo, and has a favorable number needed to treat.

Abstract

Few controlled studies are available to guide the clinician in treating potentially assaultive elderly individuals with psychiatric disorders. Safety concerns limit the use of benzodiazepines and antipsychotic medications in the elderly individual, making anticonvulsants an attractive alternative. This paper reviews three specific anticonvulsants for this purpose: gabapentin, oxcarbazepine and topiramate, describing safety and efficacy in elderly patients with severe agitation from psychosis or dementia. Gabapentin, renally excreted, with a half-life of 6.5-10.5 h, may cause ataxia. Oxcarbazapine, hepatically reduced, may cause hyponatremia, and topiramate may cause significant cognitive impairment. Nonetheless, these are important medications to consider in the treatment of agitation.

Abstract

Bipolar disorder is a chronic, severe condition commonly causing substantial mortality and psychosocial morbidity. Challenges in recognition can delay the institution of appropriate management, whereas misdiagnosis may initiate pharmacologic interventions that adversely affect the condition's course. Pharmacotherapy remains the foundation of treatment. In addition to efficacy, tolerability is an important consideration in medication choice, particularly for long-term maintenance because of its impact on adherence. Mood stabilizers are the classic treatments for bipolar disorder. Newer agents such as atypical antipsychotics may offer efficacy and/or tolerability advantages compared with other medications. The role of antidepressants in bipolar disorder remains controversial. Growing evidence indicates that adjunctive psychosocial interventions improve long-term functioning; consequently, psychologists are becoming increasingly involved in the long-term care of patients with bipolar disorder. This review seeks to update psychologists and related healthcare professionals on recent advances and the current limitations in the diagnosis and treatment of bipolar disorder.

Abstract

Carbamazepine began to be studied in a systematic fashion in the 1970s and became more widely used in the treatment of bipolar disorder in the 1980s. Interest in carbamazepine has been renewed by (i) the recent US FDA approval of a long-acting preparation for the treatment of acute mania; (ii) studies suggesting some efficacy in bipolar depression; and (iii) evidence of prophylactic efficacy in some difficult-to-treat subtypes of bipolar illness. A series of double-blind controlled studies of the drug were conducted at the US National Institute of Mental Health from the mid-1970s to the mid-1990s. This review summarises our experience in the context of the current literature on the clinical efficacy, adverse effects and pharmacokinetic interactions of carbamazepine. Carbamazepine has an important and still evolving place in the treatment of acute mania and long-term prophylaxis. It may be useful in individuals with symptoms that are not responsive to other treatments and in some subtypes of bipolar disorder that are not typically responsive to a more traditional agent such as lithium. These subtypes might include those patients with bipolar II disorder, dysphoric mania, substance abuse co-morbidity, mood incongruent delusions, and a negative family history of bipolar illness in first-degree relatives. In addition, carbamazepine may be useful in patients who do not adequately tolerate other interventions as a result of adverse effects, such as weight gain, tremor, diabetes insipidus or polycystic ovarian syndrome. We review our clinical and research experience with carbamazepine alone and in combination with lithium, valproic acid and other agents in complex combination treatment of bipolar illness. More precise clinical and biological predictors and correlates of individual clinical responsiveness to carbamazepine and other mood stabilisers are eagerly awaited.

Abstract

To assess the perceptions of clinicians in the psychiatric community about pharmacotherapy and its impact on weight gain and adverse metabolic effects in patients with bipolar disorder.In November 2005, self-administered questionnaires were sent to 7000 psychiatrists who treat bipolar disorder in their clinical practice. An additional mailing of these questionnaires was sent in January 2006 to a different group of 7000 psychiatrists who treat bipolar disorder in their clinical practice. The first 298 completed surveys were analyzed.Almost half of the respondents (48%) were psychiatrists in individual private practice and 32% were in community mental health centers. About two-thirds of respondents reported that 30-60% of their bipolar patients were overweight. Thirty-eight percent of respondents reported metabolic syndrome present in 20-40% of their patients. Almost all respondents (96%) reported a 20 lb increase in patients' weight as a troublesome potential adverse event associated with the use of some agents. After initiating a new medication, more than 80% of respondents monitored their patients' weight, fasting plasma glucose level, and fasting lipid profile at regular intervals. However, 80% did not monitor waist circumference. Overall, respondents viewed several agents (aripiprazole, ziprasidone, carbamazepine, and lamotrigine) as not (or minimally) problematic in terms of weight gain and adverse metabolic concerns. Clozapine and olanzapine were viewed as highly problematic due to their propensity to induce weight gain and negatively influence lipid and glucose metabolism. Other agents considered to be minimally to moderately problematic in terms of weight gain and metabolic issues were quetiapine, risperidone, lithium, and valproate. Respondents reported that the profile of a bipolar agent in terms of weight gain and adverse metabolic effects was an important consideration in the management of bipolar disorder.Although the study is limited by a low response rate and self-selection of respondents, clinicians who did respond were concerned about the risks of weight gain and metabolic disturbances in their patients treated with bipolar agents. For most parameters, such concerns were being integrated into clinical care. However, it appears that there is a need to increase clinicians' appreciation of the importance of abdominal obesity and the need to monitor waist circumference. A growing recognition of the differences in weight-gain potential and adverse metabolic effects among agents appears to have had a definite impact on prescribing patterns in the management of bipolar disorder.

Abstract

Subsyndromal symptoms in bipolar disorder can cause significant functional impairment and are associated with relapse.In this post hoc analysis from 2 randomized, double-blind, 18-month, placebo-controlled maintenance trials for bipolar I disorder (both trials were conducted between August 1997 and August 2001 and used DSM-IV criteria), the incidence, time course, and impact of pharmacotherapy on subsyndromal symptoms were examined.Subsyndromal symptoms occurred in approximately 25% of all visits. Compared with placebo (54.8%), a significantly higher mean percentage of visits in remission were observed with lamotrigine treatment (63.0%, p = .020) but not with lithium treatment (60.0%, p = .165). The median time to onset of subsyndromal symptoms for lamotrigine (N = 223), lithium (N = 164), and placebo (N = 188) was 15, 15, and 9 days, respectively. Compared with placebo, both lamotrigine and lithium significantly delayed the time from randomization to onset of subsyndromal symptoms (p = .046, lamotrigine vs. placebo; p = .033, lithium vs. placebo; p = .763, lamotrigine vs. lithium) and the time from onset of subsyndromal symptoms to subsequent mood episode (p = .037, lamotrigine vs. placebo; p = .023, lithium vs. placebo; p = .845, lamotrigine vs. lithium). Agreement between the polarities of the first-observed subsyndromal symptom and subsequent intervention for mood episode was statistically significant (p < .001).Subsyndromal symptoms are common during maintenance treatment and appear to be associated with relapse into an episode of the same polarity. Both lithium and lamotrigine delayed the onset of subsyndromal symptoms and the time from onset of subsyndromal symptoms to subsequent relapse. Further study to assess whether treatment intervention can minimize subsyndromal symptoms or prevent relapse is encouraged.

Abstract

Several lines of evidence suggest that omega-3 fatty acids may be important in the pathophysiology, treatment or prevention of bipolar disorder (BD). Electronic and manual searches were conducted in order to review the literature relevant to the etiology and treatment of BDs with omega-3 fatty acids. We also present data from a randomized, double-blind, placebo-controlled pilot study conducted at three sites (N = 10) comparing an omega-3 fatty acid (docosahexaenoic acid, DHA) versus placebo, added to psychosocial treatment for women with BD who chose to discontinue standard pharmacologic treatment while attempting to conceive. While some epidemiologic and preclinical data support the role of omega-3 fatty acids in BD, clinical trials to date have yielded conflicting results. In our pilot study of 10 Caucasian women taking DHA while attempting to conceive (BP1 = 9, BPII = 1), age 27-42 years, DHA was well tolerated and suggests that a larger study would be feasible. The elucidation of the potential role of omega-3 fatty acids as a treatment for BD requires further study. The current data are not sufficient to support a recommendation of monotherapy treatment as a substitute for standard pharmacologic treatments. However, judicious monotherapy in selected clinical situations, or adjunctive use, may be warranted pending further data from adequately powered controlled clinical trials. Our pilot trial of DHA in women who plan to stop conventional psychotropics in order to conceive suggests that such trials are feasible.

Abstract

Antiepileptic drugs (AEDs) have diverse psychotropic profiles. Some AEDs have proven to be efficacious in the treatment of mood disorders, especially bipolar disorder. Others are ineffective as primary treatments but may be useful adjuncts for mood disorders or comorbid conditions. Valproate (acute mania and mixed episodes), carbamazepine (acute mania and mixed episodes), and lamotrigine (maintenance to delay recurrence) have United States Food and Drug Administration indications for the treatment of bipolar disorder. This article provides an overview of data on the use of AEDs in bipolar disorder, including acute mania and depression, prophylaxis, and rapid cycling.

Abstract

There are an increasing number of pharmacologic therapies for bipolar disorder. Two of these agents, the anticonvulsants carbamazepine (CBZ) and valproate (VPA), were first developed over 30 years ago for the treatment of epilepsy, and subsequent studies demonstrated that they are also effective in the treatment of acute mania and suggest efficacy as maintenance therapy in bipolar disorder. Because VPA and CBZ have been in use for many years, the psychiatric community is familiar with the adverse event profiles of these agents. A review of the clinical data evaluating VPA and CBZ monotherapy for the treatment of acute mania suggests that VPA and CBZ are similarly effective in acute mania. However, when their respective adverse event profiles are considered, VPA may be more tolerable than CBZ for short-term use, while CBZ may be better suited for long-term therapy. Controlled and direct comparative studies, both short and long term, are needed to further clarify the differences between VPA and CBZ.

Abstract

This study assessed weight changes in a large cohort of patients with bipolar disorder who were treated with randomly assigned maintenance monotherapies.A post hoc analysis was conducted to assess the effects of lamotrigine, lithium, and placebo administration on body weight in obese and nonobese patients with bipolar disorder from two double-blind, placebo-controlled, 18-month studies.Mean changes in weight among obese patients (N=155) at week 52 were -4.2, +6.1, and -0.6 kg with lamotrigine, lithium, and placebo, respectively (lamotrigine versus lithium and lithium versus placebo). Among nonobese patients (N=399), mean changes in weight (kg) at week 52 were -0.5, +1.1, and +0.7 with lamotrigine, lithium, and placebo, respectively, with no significant differences among groups.Obese patients with bipolar I disorder lost weight while taking lamotrigine and gained weight while taking lithium.

Abstract

To assess the relations between sustained attention as assessed by the Continuous Performance Test (CPT) and subgenual and dorsolateral prefrontal cortex metabolism in depressed patients with bipolar disorders and healthy controls.Cross-sectional case-control design.Cerebral metabolic rates were assessed with 18F-fluoro-deoxyglucose and positron emission tomography (PET) in the regions of interest defined on co-registered structural magnetic resonance images in eight medication-free, depressed bipolar disorder patients and 27 healthy control participants. PET scans were obtained in a resting state and the CPT was administered within 1 week of the PET scan.Although there were no statistically significant differences in performance on the CPT or in cerebral metabolism between the two groups, our analyses revealed differential relations between the CPT and metabolism across the groups. Decreased subgenual prefrontal metabolism was associated with slower hit rate reaction time and more omission errors in the bipolar group, but not the control group. Decreased dorsolateral prefrontal metabolism in the bipolar group, but not the control group, was associated with more commission errors.This study extends previous neuroimaging findings of structural and functional relevance of the prefrontal region with attention to include depressed states in bipolar disorder. The results are consistent with interpretations that decreased prefrontal activity may represent failure to activate some areas of inhibitory control. Decreasing subgenual prefrontal cortex metabolism appears to relate to decreased attention whereas the decreased dorsolateral prefrontal cortex metabolism relates more to decreased inhibitory control.

Abstract

To assess the efficacy of lamotrigine or lithium in preventing mood recurrence (i.e., a new mood episode) in bipolar disorder.Data from bipolar I patients with relapses (i.e., mood episodes having the same polarity as the index episode within 90 or 180 days of randomization) were excluded from post hoc efficacy analyses of two 18-month, placebo-controlled maintenance trials of lamotrigine and lithium.Both lamotrigine and lithium were more effective than placebo in delaying the time to intervention for any mood episode (depression, mania, hypomania, or mixed) when relapses that occurred in the first 90 days were excluded from the analyses (p = .002, lamotrigine vs. placebo; p = .010, lithium vs. placebo). Results were similar when patients with mood episodes within 180 days of randomization were excluded.Both lamotrigine and lithium maintenance therapy protected against mood episode recurrence in bipolar I disorder.

Abstract

The authors review current research on the safety and tolerability of anticonvulsant medications used for individuals over the age of 60 years with affective disorders, agitation and other psychiatric disorders. Three anticonvulsants currently approved in the US for treatment of bipolar affective disorder are reviewed: valproate, lamotrigine and extended-release carbamazepine. The authors discuss the pharmacokinetics, pharmacodynamics, drug-drug interactions and the impact of ageing for each drug. There are few studies of anticonvulsant medications in elderly patients with bipolar disorder or other psychiatric conditions. Therefore, the authors summarise adverse events of greatest prevalence and/or greatest severity based on data derived predominately from studies of geriatric patients with epilepsy and/or other non-psychiatric indications. Guidelines are offered for the safe use of these medications in the elderly, based on research literature.

Abstract

The effect of lamotrigine maintenance therapy on body weight was assessed retrospectively in analyses of data from two double-blind, placebo- and lithium-controlled, 18-month studies in patients with bipolar I disorder (n = 227 for lamotrigine, 190 for placebo, 166 for lithium).Endpoints included mean change in weight, the percentage of patients with > or = 7% change (increase, decrease, fluctuation) in weight, and the percentage of patients with weight-related adverse events during double-blind treatment.Mean weight remained stable during maintenance therapy with lamotrigine. In a mixed-model repeated-measures analysis, mean changes in weight (kg) at week 52 were -1.2 with lamotrigine, +0.2 with placebo, and +2.2 with lithium [estimated difference (95% CI) lamotrigine minus placebo = -1.3 (-3.6, 0.9), p = 0.237; lithium minus placebo = +2.0 (-0.3, 4.4), p = 0.094; lithium minus lamotrigine = +3.4 (1.4, 5.4), p < 0.001]. Analyses were truncated at week 52 because of the high incidence of missing data at later time points. The percentages of patients with a >/=7% weight gain, during randomized treatment, were 10.9%, 7.6% and 11.8% for the lamotrigine, placebo, and lithium groups, respectively. The percentages of patients with a > or = 7% weight loss, during randomized treatment, were 12.1%, 11.5%, and 5.1% for the lamotrigine, placebo, and lithium groups, respectively. The percentage of patients with a > or = 7% weight loss did not significantly differ between lamotrigine and placebo but was significantly higher with lamotrigine than lithium. The incidences of > or = 7% weight changes and of weight changes reported as adverse events were comparable between active treatments and placebo.Lamotrigine was associated with stable body weight during 1 year of treatment and was comparable to placebo in mean weight change, incidence of clinically significant weight change, and incidence of weight changes reported as adverse events in patients with bipolar disorder. Lithium was associated with weight gain, but the magnitude of lithium-associated weight gain was lower in the current analysis than in previous studies.

Abstract

Prescribing recommendations specify that lamotrigine should ordinarily be discontinued at the first sign of rash, regardless of its type and severity, unless the rash is clearly not drug related. This practice helps to ensure that lamotrigine is discontinued in instances of serious rash (an event occurring in up to 0.13% of cases in bipolar clinical trials) but may lead to unnecessary discontinuation of lamotrigine for cases of nonserious rash arising from nondrug causes. Measures aimed at reducing overall occurrence of dermatologic reactions might reduce the incidence of nonserious rash leading to premature lamotrigine discontinuation. This study assessed the impact of specific instructions designed to decrease risk of dermatologic reactions, including nonserious rash, during initiation of and early treatment with lamotrigine in patients with bipolar I disorder.Outpatients with DSM-IV-diagnosed bipolar I disorder >/= 13 years of age at 188 sites were randomly assigned to receive Usual Care Precautions (UCP; precautions from the patient instructions in the prescribing information for reducing risk of rash including nonserious rash) or Dermatologic Precautions (DP; precautions as above [UCP] plus additional precautions intended to decrease risk of any dermatologic reaction including nonserious rash) during 12 weeks of adding open-label lamotrigine to concomitant medications. Patients with comorbid medical and psychiatric problems were not excluded unless, in the opinion of the investigators, these problems were sufficiently severe to preclude participation. Investigators and patients were blinded to which precaution group patients were randomly assigned. The primary outcome measure was the rate of rash during the treatment period. Secondary outcome measures included clinical response to lamotrigine, assessed with the investigator- and self-rated Clinical Global Impressions-Bipolar version (CGI-BP) and the Clinical Global Impressions-Efficacy Index (CGI-EI). Data were collected from August 2003 to August 2004.867 (74%) of 1175 patients completed the study. Only 182 (15%) of 1175 patients had an adverse event leading to discontinuation of study medication or withdrawal, including 62 (5.3%) of 1175 due to non-serious rash. No serious rashes were reported during the study in either group. The incidence of nonserious rash was similarly low in patients with UCP and DP (8.8% and 8.6%, respectively). CGI-BP-Severity and -Improvement scores indicated mood improvement when lamotrigine was added to existing therapy, and CGI-EI scores at weeks 5 and 12 reflected a favorable balance between control of mood symptoms and tolerability. At both weeks 5 and 12, investigators reported that therapeutic effects of additional lamotrigine outweighed side effects in 74% of subjects.UCP and DP yielded low, similar non-serious rash rates, which were marginally lower than nonserious rash rates in prior clinical trials that did not utilize DP but marginally higher than that in a prior open case series using DP. Nevertheless, the results are encouraging: in this large study reflecting real-world use, lamotrigine was well tolerated with no serious rash and low incidences of nonserious rash and discontinuation due to rash, and lamotrigine therapy was associated with clinical improvement in a heterogeneous cohort of patients with bipolar I disorder.

Abstract

Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence.The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression.Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416 (48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence.Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence.

Abstract

Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone.Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks.No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone.No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression.

Abstract

Recently, two large, 3-week, randomised, double-blind, placebo-controlled trials using nearly identical protocols demonstrated that monotherapy with carbamazepine extended-release capsules (CBZ-ERC) was effective for the treatment of acute mania in patients with bipolar I disorder. By pooling data from these two trials, a more highly powered analysis of the efficacy and safety of CBZ-ERC in bipolar I disorder could be conducted.Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Clinical Global Impression (CGI)-Severity (CGI-S) scale, the CGI-Improvement (CGI-I) scale and the Hamilton Depression Rating Scale (HDRS). A sub-analysis of the data based on manic versus mixed presentation was performed, as well as sub-analyses by age, sex and ethnicity.Of the 443 randomised patients in the pooled population, 240 completed the studies. Forty-two percent of CBZ-ERC-treated patients did not complete the studies, compared with 50% of placebo-treated patients (p=0.087). Ten percent of patients given CBZ-ERC withdrew because of lack of efficacy, compared with 22% of patients given placebo (p<0.001). At endpoint, CBZ-ERC compared with placebo was associated with significant improvements in mean YMRS total scores in patients experiencing both manic (p<0.0001) and mixed (p<0.01) episodes, using last-observation-carried-forward analyses. CGI-I and CGI-S scores also showed significant improvements from baseline for both manic and mixed patients at endpoint. In patients with mixed episodes, at endpoint there was a mean improvement in HDRS total score of 4.8 points with CBZ-ERC, compared with 2.3 points with placebo (p<0.05). Ninety percent of patients given CBZ-ERC experienced an adverse event, compared with 64% of those patients given placebo. Discontinuation because of adverse events occurred in 10.8% of patients taking CBZ-ERC, compared with 5.5% of patients taking placebo.These results confirm previous findings that CBZ-ERC is effective in the treatment of bipolar I disorder patients with either acute manic or mixed episodes. These data suggest that further randomised controlled studies are warranted to delineate the effect of CBZ-ERC on depressive symptoms in patients with bipolar disorder.

Abstract

Treatment options for bipolar disorder have rapidly expanded over the last decade, but providing optimal management remains an elusive goal. The authors reviewed the literature on the efficacy of agents with the best clinical evidence supporting their use in bipolar disorder, including the mood stabilizers lithium, valproate, lamotrigine, and carbamazepine, as well as the atypical antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Most medications appear to be more effective for symptoms of mood elevation than for symptoms of depression. The efficacy, tolerability, and safety profiles of agents must be considered when making clinical decisions. Several agents, including lithium, valproate, olanzapine, quetiapine, and risperidone, can cause problematic weight gain. In addition, the use of atypical antipsychotics has been associated with an increased risk of metabolic abnormalities such as dyslipidemia, hypergylycemia, and diabetes mellitus. In most patients, monotherapy offers inadequate efficacy. Further investigation of combinations of agents such as mood stabilizers and atypical antipsychotics may yield valuable insights into the potential of combination therapies to enhance clinical outcomes in patients with bipolar disorder.

Abstract

Two recently completed large, randomised, double-blind, placebo-controlled trials supporting the efficacy of carbamazepine (CBZ) extended-release capsules (ERC) for the treatment of acute manic and mixed episodes have resulted in US FDA approval of CBZ-ERC, and have reinvigorated the importance of understanding the role of CBZ in bipolar disorder (BD) pharmacotherapy. Additional data suggest that CBZ may have a use in BD maintenance treatment and possibly in acute BD depression. Optimal use of CBZ requires sound knowledge of adverse effects and pharmacokinetic interactions with this agent. Adverse effects commonly involve benign side effects but can rarely include serious haematological, dermatological and hepatic manifestations. On the other hand, metabolic adverse effects (thyroid, glucose, lipid disturbances and significant weight gain) can be less problematic with CBZ, compared with lithium, valproate and atypical antipsychotics. Pharmacokinetic considerations (cytochrome P450 3A3/4 metabolism, active epoxide metabolite and catabolic enzyme induction) can influence the clinical use of CBZ. Managing adverse effects and pharmacokinetic complexities is important for optimising pharmacotherapy with CBZ in patients with BD. This paper reviews the chemistry, pharmacodynamics and pharmacokinetics of CBZ, as well as reviews of the controlled trials of CBZ in acute bipolar mania, acute bipolar depression and bipolar maintenance treatment.

Abstract

Cerebral metabolism (CMR for glucose or oxygen) and blood flow (CBF) have been reported to be closely correlated in healthy controls. Altered relationships between CMR and CBF have been reported in some brain disease states, but not others. This study examined relationships between global and regional CMRglu vs. CBF in controls and medication-free primary affective disorder patients. Nine bipolars, eight unipolars, and nine healthy controls had [15O]-water positron emission tomography (PET) scans at rest, and [18F]-fluorodeoxyglucose PET scans during an auditory continuous performance task. Patients had [15O]-water and FDG PET scans in tandem the same day; controls had an average of 45+/-27 days between scans. Maps of regional coupling were constructed for each subject group. In controls and bipolars, global and virtually all regional correlation coefficients for CMRglu and CBF were positive, albeit more robustly so in controls. However, correlative relationships in unipolars were qualitatively different, such that global and most regional measures of flow and metabolism were not positively related. Unipolars had significantly fewer positive regional correlation coefficients than healthy controls and bipolars. These were significantly different from controls in orbital cortex, anterior cingulate, posterior cingulate, and posterior temporal cortex, and different from bipolars in pregenual anterior cingulate. In unipolars, the degree of flow-metabolism uncoupling was inversely correlated with Hamilton depression scores, indicating the severity of uncoupling was directly related to the severity of depression. These preliminary data suggest abnormal relationships between cerebral metabolism and blood flow globally and regionally in patients with unipolar depression that warrant replication and extension to potential pathophysiological implications.

Abstract

Studies have demonstrated relationships between creativity and bipolar disorder (BD) in individuals, and suggested familial transmission of both creativity and BD. However, to date, there have been no studies specifically examining creativity in offspring of bipolar parents and clarifying mechanisms of intergenerational transmission of creativity. We compared creativity in bipolar parents and their offspring with BD and bipolar offspring with attention-deficit/hyperactivity disorder (ADHD) with healthy control adults and their children. 40 adults with BD, 20 bipolar offspring with BD, 20 bipolar offspring with ADHD, and 18 healthy control parents and their healthy control children completed the Barron-Welsh Art Scale (BWAS), an objective measure of creativity. Adults with BD compared to controls scored significantly (120%) higher on the BWAS Dislike subscale, and non-significantly (32%) higher on the BWAS Total scale. Mean BWAS Dislike subscale scores were also significantly higher in offspring with BD (107% higher) and offspring with ADHD (91% higher) than in healthy control children. Compared to healthy control children, offspring with BD had 67% higher and offspring with ADHD had 40% higher BWAS Total scores, but these differences failed to reach statistical significance when adjusted for age. In the bipolar offspring with BD, BWAS Total scores were negatively correlated with duration of illness. The results of this study support an association between BD and creativity and contribute to a better understanding of possible mechanisms of transmission of creativity in families with genetic susceptibility for BD. This is the first study to show that children with and at high risk for BD have higher creativity than healthy control children. The finding in children and in adults was related to an enhanced ability to experience and express dislike of simple and symmetric images. This could reflect increased access to negative affect, which could yield both benefits with respect to providing affective energy for creative achievement, but also yield liabilities with respect to quality of interpersonal relationships or susceptibility to depression.

Abstract

Morphometric magnetic resonance imaging (MRI) studies of pediatric bipolar disorder (BD) have not reported on gray matter volumes but have reported increased lateral ventricular size and presence of white matter hyperintensities (WMH). We studied gray matter volume, ventricular-to-brain ratios (VBR), and number of WMH in patients with familial, pediatric BD compared with control subjects.Twenty subjects with BD (aged 14.6 +/- 2.8 years; 4 female) according to the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, each with a parent with BD, and 20 age-, gender-, and intelligence quotient-matched healthy control subjects (aged 14.1 +/- 2.8 years; 4 female) were scanned at 3 T. Most subjects were taking psychotropic medications. A high-resolution T1-weighted spoiled gradient echo three-dimensional MRI sequence was analyzed by BrainImage for volumetric measurements, and T2-weighted images were read by a neuroradiologist to determine presence of WMH.After covarying for age and total brain volume, there were no significant differences between subjects with BD and control subjects in volume of cerebral (p = .09) or prefrontal gray matter (p = .34). Subjects with BD did not have elevated numbers of WMH or greater VBR when compared with control subjects.Children and adolescents with familial BD do not seem to have decreased cerebral grey matter or increased numbers of WMH, dissimilar to findings in adults with BD. Gray matter decreases and development of WMH might be later sequelae of BD or unique to adult-onset BD.

Abstract

A panel consisting of academic psychiatrists and pharmacist administrators of the Texas Department of State Health Services (formerly Texas Department of Mental Health and Mental Retardation), community mental health physicians, advocates, and consumers met in May 2004 to review new evidence in the pharmacologic treatment of bipolar I disorder (BDI). The goal of the consensus conference was to update and revise the current treatment algorithm for BDI as part of the Texas Implementation of Medication Algorithms, a statewide quality assurance program for the treatment of major psychiatric illness. The guidelines for evaluating possible medications, the criteria for selection and ranking, and the updated algorithms are described.Principles from previous consensus conferences were reviewed and amended. Medication algorithms for the acute treatment of hypomanic/manic or mixed and depressive episodes in BDI were developed after examining recent efficacy and safety and tolerability data. Recommendations for maintenance treatments were developed.The panel updated the 2 primary algorithms (hypomanic/manic/mixed and depressive) based on clinical evidence for efficacy, tolerability, and safety developed since 2000. Expert consensus was utilized where clinical evidence was limited. Prevention of new episodes or prophylaxis treatment recommendations were developed based on recent data from longer-term trials. Maintenance recommendations are provided as levels versus a specified staged algorithm, as for acute treatment, due to the relatively limited database to inform treatment.These algorithms for the treatment of BDI represent the recommendations based on the most recent evidence available. These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available.

Abstract

There is a major unmet need for effective options in the treatment of bipolar depression.Five hundred forty-two outpatients with bipolar I (N=360) or II (N=182) disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 8 weeks of quetiapine (600 or 300 mg/day) or placebo. The primary efficacy measure was mean change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale total score. Additional efficacy assessments included the Hamilton Depression Rating Scale, Clinical Global Impression of severity and improvement, Hamilton Anxiety Rating Scale, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire.Quetiapine at either dose demonstrated statistically significant improvement in Montgomery-Asberg Depression Rating Scale total scores compared with placebo from week 1 onward. The proportions of patients meeting response criteria (> or =50% Montgomery-Asberg Depression Rating Scale score improvement) at the final assessment in the groups taking 600 and 300 mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for placebo. The proportions of patients meeting remission criteria (Montgomery-Asberg Depression Rating Scale < or =12) were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at 600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg Depression Rating Scale items, respectively, compared to placebo, including the core symptoms of depression. Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups (3.2% and 3.9%, respectively).Quetiapine monotherapy is efficacious and well tolerated for the treatment of bipolar depression.

Abstract

This monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions. Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

Abstract

To assess treatment-emergent rash incidence when using dermatology precautions (limited antigen exposure) and slower titration during lamotrigine initiation.We assessed rash incidence in 100 patients with DSM-IV bipolar disorder instructed, for their first 3 months taking lamotrigine, to avoid other new medicines and new foods, cosmetics, conditioners, deodorants, detergents, and fabric softeners, as well as sunburn and exposure to poison ivy/oak. Lamotrigine was not started within 2 weeks of a rash, viral syndrome, or vaccination. In addition, lamotrigine was titrated more slowly than in the prescribing information. Patients were monitored for rash and clinical phenomena using the Systematic Treatment Enhancement Program for Bipolar Disorder Clinical Monitoring Form. Descriptive statistics were compiled.No patient had serious rash. Benign rash occurred in 5 patients (5%) and resolved uneventfully in 3 patients discontinuing and 2 patients continuing lamotrigine. Two patients with rash were found to be not adherent to dermatology precautions. Therefore, among the remaining patients, only 3/98 (3.1%) had benign rashes.The observed rate of benign rash was lower than the 10% incidence in other clinical studies. The design of this study confounds efforts to determine the relative contributions of slower titration versus dermatology precautions to the low rate of rash. Systematic studies are needed to confirm these preliminary findings, which suggest that adhering to dermatology precautions with slower titration may yield a low incidence of rash with lamotrigine.

Abstract

Understanding of mood disorders can be enhanced through assessment of temperamental traits. We explored temperamental commonalities and differences among euthymic bipolar (BP) and unipolar (MDD) mood disorder patients, creative discipline graduate student controls (CC), and healthy controls (HC).Forty-nine BP, 25 MDD, 32 CC, and 47 HC completed self-report temperament/personality measures including: The Affective Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A); the Revised NEO Personality Inventory (NEO-PI-R); and the Temperament and Character Inventory (TCI).Euthymic BP, MDD, and CC, compared to HC, had significantly increased cyclothymia, dysthymia and irritability scores on TEMPS-A; increased neuroticism and decreased conscientiousness on NEO-PI-R; and increased harm avoidance and novelty seeking as well as decreased self-directedness on TCI. TEMPS-A cyclothymia scores were significantly higher in BP than in MDD. NEO-PI-R openness was increased in BP and CC, compared to HC, and in CC compared to MDD. TCI self-transcendence scores in BP were significantly higher than in MDD, CC, and HC.Most of the subjects were not professional artists, and represented many fields; temperament might be different in different art fields.Euthymic BP, MDD, and CC compared to HC, had prominent temperamental commonalities. However, BP and CC had the additional commonality of increased openness compared to HC. BP had particularly high Cyclothymia scores that were significantly higher then those of MDD. The prominent BP-CC overlap suggests underlying neurobiological commonalities between people with mood disorders and individuals involved in creative disciplines, consistent with the notion of a temperamental contribution to enhanced creativity in individuals with bipolar disorders.

Abstract

Although carbamazepine has long been used for the treatment of acute mania, only recently was its efficacy confirmed in a large, multicenter, parallel-group, placebo-controlled, randomized trial. In the present study, we further evaluated the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ) in patients with bipolar I disorder experiencing manic or mixed episodes.Hospitalized bipolar I disorder (DSM-IV criteria) patients (N = 239) with manic or mixed episodes were randomly assigned on a double-blind basis to receive ERC-CBZ or placebo for 3 weeks, following a single-blind placebo lead-in. Treatment with ERC-CBZ was initiated at 200 mg twice daily, and investigators were encouraged to increase doses, as necessary and tolerated, by 200 mg/day up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression. The study was conducted from July 23, 2002, to April 1, 2003.144 patients (60.3%) completed the study, with a significant number of placebo patients discontinuing due to lack of efficacy (p < .001). Extended-release carbamazepine treatment was associated with significant improvements in mean YMRS total and CGI total scores, using last-observation-carried-forward analyses, beginning at day 7 (p < .05). Adverse events occurring more frequently in the ERC-CBZ-treated group included dizziness (39.3%), somnolence (30.3%), and nausea (23.8%) [corrected] Patients taking ERC-CBZ experienced a significant increase in total cholesterol, composed of increases in both high-density and low-density lipoproteins.Extended-release carbamazepine monotherapy had significantly greater efficacy compared with placebo in the treatment of acute mania in this large, randomized, double-blind, placebo-controlled trial.

Abstract

Pretreatment functional brain imaging was examined for never-hospitalized outpatients with unipolar depression compared with control subjects in a crossover treatment trial involving bupropion or venlafaxine monotherapy.Patients (n = 20) with unipolar depression received baseline (medication-free) fluorine-18 deoxyglucose (FDG) positron emission tomography (PET) scan and then at least 6 weeks of bupropion or venlafaxine monotherapy in a single-blind crossover trial. Age-matched healthy control subjects (n = 20) also received baseline FDG PET scans. For each medication PET data from patients compared with control subjects was analyzed as a function of treatment response (defined as moderate to marked improvement on the Clinical Global Impression Scale).Treatment response rates were similar for buproprion (32%) and venlafaxine (33%). Compared with control subjects, responders but not nonresponders, to both drugs demonstrated frontal and left temporal hypometabolism. Selectively, compared with control subjects bupropion responders (n = 6) also had cerebellar hypermetabolism, whereas venlafaxine responders (n = 7) showed bilateral temporal and basal ganglia hypometabolism.These data suggest that pretreatment frontal and left temporal hypometabolism in never-hospitalized depressed outpatients compared with control subjects is linked to positive antidepressant response and that additional alterations in regional metabolism may be linked to differential responsivity to bupropion and venlafaxine monotherapy.

Abstract

The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n = 182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.

Abstract

Bipolar disorder is a severe, recurrent, and often highly impairing psychiatric disorder. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is a large-scale multicenter study funded by the National Institute of Mental Health (NIMH) to examine the longitudinal course of the disorder and the effectiveness of current treatments. The current report provides a context for interpreting studies resulting from STEP-BD by summarizing the baseline demographic and diagnostic characteristics of the first 1000 enrolled.The majority of the sample met DSM-IV criteria for bipolar I disorder (71%). Mean age of patients was 40.6 (+/-12.7) years and mean duration of bipolar illness was 23.1 (+/-12.9) years. Among the first 1000 subjects enrolled, 58.6% are females and 92.6% Caucasian. This report compares the STEP-BD sample with other large cohorts of bipolar patients (treatment and community samples).Compared with US population and community studies, the first 1000 STEP-BD patients were less racially diverse, more educated, had lower income, and a higher unemployment rate. Results are discussed in terms of the contributions of STEP-BD (and other large-scale treatment studies) in understanding the nature, treatments, and outcomes of bipolar disorder for patients seeking care at academic treatment centers.The current report provides a context for interpreting future studies resulting from STEP-BD. The comparison of demographic and clinical characteristics between the samples across clinic-based studies suggests broad similarities despite the substantial differences in geography, payer mix, and clinical entry point.

Abstract

Few controlled studies examine the treatment of depressive features in mania.To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania.Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5-20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients.In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy.In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings.

Abstract

To evaluate lamotrigine in a woman with a 30-year history of treatment-resistant menstrually-entrained rapid cycling bipolar II disorder with follicular phase depressive and luteal phase mood elevation symptoms.Lamotrigine was started at 5 mg/day and gradually increased up to 300 mg/day, while venlafaxine was tapered gradually and discontinued, and divalproex sodium 500 mg/day and levothyroxine 175 mcgm/day were continued. Daily self-reported mood ratings were obtained from the patient, using ChronoRecord software.As lamotrigine was increased gradually, mood cycle amplitude attenuated. There was notable decrease in the severity and duration of depressive symptoms specifically during the follicular phase of the menstrual cycle. At the time of submission of this paper, the subject had remained euthymic for a total of 12 months.This case suggests the potential utility of lamotrigine in treatment-resistant menstrually-related rapid cycling bipolar disorder, and raises the possibility that lamotrigine might be able to treat pathological entrainment of mood with the menstrual cycle. Both of these issues merit systematic assessment.

Abstract

This study compared demographic and phenomenological variables between bipolar patients with and without rapid cycling as a function of bipolar I versus bipolar II status.The authors examined demographic, historical, and symptomatic features of patients with and without rapid cycling in a cross-sectional study of the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder.Rapid-cycling bipolar disorder occurred in 20% of the study group. Rapid-cycling patients were more likely to be women, although the effect was somewhat more pronounced among bipolar I patients than bipolar II patients. In addition, rapid-cycling bipolar patients experienced onset of their illness at a younger age, were more often depressed at study entry, and had poorer global functioning in the year before study entry than nonrapid-cycling patients. Rapid-cycling patients also experienced a significantly greater number of depressive and hypomanic/manic episodes in the prior year. A lifetime history of psychosis did not distinguish between rapid and nonrapid-cycling patients, although bipolar I patients were more likely to have experienced psychosis than bipolar II patients.Patients with rapid-cycling bipolar disorder demonstrate a greater severity of illness than nonrapid-cycling patients on a number of clinical measures. This study highlights the need to refine treatments for rapid cycling to reduce the overall morbidity and mortality of patients with this illness course modifier.

Abstract

The local anesthetic procaine, when administered to humans intravenously (i.v.), yields brief intense emotional and sensory experiences, and concomitant increases in anterior paralimbic cerebral blood flow, as measured by positron emission tomography (PET). Procaine's high muscarinic affinity, together with the distribution of muscarinic receptors that overlaps with brain regions activated by procaine, suggests a muscarinic contribution to procaine's emotional and sensory effects. This study evaluates the effects of procaine on cerebral muscarinic cholinergic receptors in the anesthetized rhesus monkey. Whole brain and regional muscarinic receptor binding was measured before and after procaine administration on the same day in three anesthetized rhesus monkeys with PET and the radiotracer 3-(3-(3[18F]fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP), a cholinergic ligand that has preferential binding to muscarinic (M(2)) receptors. On separate days each animal received six different doses of i.v. procaine in a randomized fashion. Procaine blocked up to approximately 90% of [18F]FP-TZTP specific binding globally in a dose-related manner. There were no regional differences in procaine's inhibitory concentration for 50% blockade (IC50) for [18F]FP-TZTP. Tracer delivery, which was highly correlated to cerebral blood flow in previous monkey studies, was significantly increased at all doses of procaine with the greatest increases occurring near procaine's IC50 for average cortex. Furthermore, anterior limbic regions showed greater increases in tracer delivery than nonlimbic regions. Procaine has high affinity to muscarinic M2 receptors in vivo in the rhesus monkey. This, as well as a preferential increase of tracer delivery to paralimbic regions, suggests that action at these receptors could contribute to i.v. procaine's emotional and sensory effects in man. These findings are consistent with other evidence of cholinergic modulation of mood and emotion.

Abstract

Carbamazepine is frequently used for treating bipolar disorder, but few large trials have assessed its efficacy in preventing relapse. We evaluated open-label monotherapy with beaded extended-release carbamazepine capsules (ERC-CBZ; SPD417) as continuation and short-term maintenance therapy in bipolar disorder patients with manic and mixed episodes.A 6-month, open-label study enrolled 92 patients with DSM-IV bipolar disorder (most recent episode: 67% [N = 62] mixed, 33% [N = 30] manic) who had participated in 2 previous 3-week, double-blind, placebo-controlled studies. Subjects received beaded ERC-CBZ (200-1600 mg/day), titrated at investigators' discretion to a final mean dose of 938 mg/day and serum carbamazepine concentration of 6.6 microg/mL. The primary efficacy measure was time to relapse, and secondary efficacy measures included Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression (HAM-D) scores. Data were gathered from January 2000 to January 2002.Of 77 patients analyzed in the intent-to-treat population, 11 (14.3%) relapsed. Fifty-three patients (68.8%) discontinued early, including 18 (23.4%) due to adverse events. Observed mean time to relapse was 61.1 days, while estimated mean time to relapse based on the Kaplan-Meier model was 141.8 days. Improvements on the YMRS, CGI, and HAM-D from the beginning of prior double-blind treatment were maintained. The most common adverse events were headache, dizziness, and rash. No significant weight gain was noted.We noted a low relapse rate with beaded ERC-CBZ in this 6-month trial. Adverse events were generally mild to moderate and were typical of those associated with carbamazepine. Controlled studies are warranted to further explore the efficacy of beaded ERC-CBZ in preventing relapse in bipolar disorder.

Abstract

Carbamazepine has been used to treat mania for over 2 decades. Most evaluations of carbamazepine have had important limitations, such as absence of a parallel placebo group, small sample size, or the confounding influence of concomitant treatment. All studies have used conventional, immediate-release carbamazepine formulations. We assessed the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ; SPD417) in bipolar disorder patients with manic or mixed episodes.Following a single-blind placebo lead-in, DSM-IV-defined bipolar disorder patients with manic or mixed episodes were randomly assigned to receive ERC-CBZ (N = 101) or placebo (N = 103) for 3 weeks. Patients were hospitalized through the first 7 days of the double-blind period. ERC-CBZ was initiated at 400 mg/day and increased, as necessary and tolerated, up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression (HAM-D). Data were gathered from December 1999 to June 2001.Ninety-six (47.1%) of 204 patients completed the study. The mean +/- SD final ERC-CBZ dose was 756.44 +/- 413.38 mg/day with a mean plasma drug level of 8.9 microg/mL. Starting at week 2, ERC-CBZ was associated with significantly greater improvements in YMRS (p =.032) using last-observation-carried-forward analyses. At end point, the responder rate (patients with at least a 50% decrease in YMRS score) also favored ERC-CBZ (41.5% vs. 22.4%; p =.0074). In a post hoc analysis of mixed patients, HAM-D score was significantly improved in patients remaining on ERC-CBZ treatment on day 21 (p =.01). Adverse events occurring more frequently in the ERC-CBZ group than in the placebo group included dizziness, nausea, and somnolence.We found ERC-CBZ to be effective in the first large, randomized, double-blind, placebo-controlled parallel trial of carbamazepine monotherapy in acute mania. This trial provides important additional evidence supporting the use of carbamazepine in acute mania.

Abstract

To describe the frequency and correlates of lamotrigine therapy among the first 500 patients enrolled into the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.Systematic recording of psychiatric history and medication data at intake into the STEP-BD project.Of the participants with bipolar disorder type I or II (n = 483), 77 (15.4%) were currently taking lamotrigine (mean dose: 258.12 mg/day) and 52 (10.4%) reported prior lamotrigine use. The groups were comparable with regard to duration of illness and mood state at study entry. Compared with participants who had never taken lamotrigine, those currently treated with lamotrigine were significantly more likely to have a prior history of rapid cycling (62.5% vs. 43.1%; p < 0.01) and an antidepressant-induced switch to (hypo)mania (49.3% vs. 33.3%; p < 0.01). In contrast, only 16.9% of lamotrigine-treated participants were taking an antidepressant at study intake, as compared with 29.1% of participants with no history of lamotrigine therapy (p < 0.03).While noting the limitations of a cross-sectional assessment, these data suggest that lamotrigine therapy was commonly used in these academic centers for patients with bipolar disorder several years before it was recommended in the American Psychiatric Association practice guidelines, particularly in patients with a history of rapid cycling or antidepressant-induced mania.

Abstract

Although patients with bipolar disorder have been shown to benefit from psychosocial interventions, the proportion that utilizes these interventions is unknown. We set out to clarify the determinants of psychosocial service utilization in adults with bipolar disorder.We investigated psychosocial service utilization among the first 500 patients admitted to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).In the 3 months prior to enrollment in STEP-BD, a majority of the patients (54%) were engaged in at least one psychosocial service modality in addition to pharmacotherapy. In order of decreasing frequency, these were therapy with a psychologist, self-help group, therapy with a social worker, and therapy with another type of provider. Bipolar patients with personality disorders (80% vs 20%, p = 0.0002), alcohol/drug abuse disorders (76% vs 24%, p = 0.0022), and anxiety disorders (60% vs 40%, p = 0.0043) received more psychosocial services than those without. Poorer global functioning also increased the likelihood of receiving services, whereas being married decreased service utilization.Psychosocial service utilization by outpatients with bipolar disorder is strongly linked to greater severity/complexity of illness. Potential moderators, such as insurance status and availability of care, should be examined in future studies.

Abstract

To assess new treatment options for bipolar disorders.Controlled studies of new treatments for bipolar disorders were identified by computerized searches and reviews of scientific meeting proceedings, and were compiled by drug category.Two main categories of medications, newer anticonvulsants and newer antipsychotics, are yielding emerging new treatment options for bipolar disorders. Newer anticonvulsants have diverse psychotropic profiles, and although not generally effective for acute mania, may have utility for other aspects of bipolar disorders (e.g. lamotrigine for maintenance or acute bipolar depression), or for comorbid conditions (e.g. gabapentin for anxiety or pain, topiramate for obesity, bulimia, alcohol dependence, or migraine, and zonisamide for obesity). In contrast, newer antipsychotics generally appear effective for acute mania, and some may ultimately prove effective in acute depression (e.g. olanzapine combined with fluoxetine, quetiapine) and maintenance (e.g. olanzapine).Emerging research is yielding new treatment options for bipolar disorders and comorbid conditions.

Abstract

For over a century, clinicians have struggled with how to conceptualize the primary psychoses, which include psychotic mood disorders and schizophrenia. Indeed, the nature of the relationship between mood disorders and schizophrenia is an area of ongoing controversy. Psychotic bipolar disorders have characteristics such as phenomenology, biology, therapeutic response, and brain imaging findings, suggesting both commonalities with and dissociations from schizophrenia. Taken together, these characteristics are in some instances most consistent with a dimensional view, with psychotic bipolar disorders being intermediate between non-psychotic bipolar disorders and schizophrenia spectrum disorders. However, in other instances, a categorical approach appears useful. Although more research is clearly necessary to address the dimensional versus categorical controversy, it is feasible that at least in the interim, a mixed dimensional/categorical approach could provide additional insights into pathophysiology and management options, which would not be available utilizing only one of these models.

Abstract

Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect g-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintenance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects. Topiramate and zonisamide may allow both weight loss, while topiramate may have specific efficacy in bulimia, binge eating disorder, and alcohol dependence. Two small studies found oxcarbazepine had similar efficacy to lithium and haloperidol in acute mania. Phenytoin, an older anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer anticonvulsant, may be worth exploring and has minimal drug-drug interactions. None of these newer agents has been shown effective in a large placebo controlled trial for acute mania. Although the clinical profiles of these newer anticonvulsants do not appear to overlap markedly with divalproex and carbamazepine (except perhaps for oxcarbazepine), these novel agents may still offer important new options in relieving a variety of specific target symptoms in patients with bipolar disorder.

Abstract

Children and adolescents who are the biological offspring of individuals with bipolar disorder (BD) (bipolar offspring) represent a population rich in potential for revealing important aspects in the development of BD. Multiple cross-sectional assessments of psychopathology in bipolar offspring have confirmed high incidences of BD, as well as mood and behavioral disorders, and other psychopathology in this population. Longitudinal studies of offspring have begun to shed light on precursors of BD development. Other assessments of bipolar offspring have included dimensional reports of psychiatric and psychosocial functioning, temperament assessments, and descriptions of family environments and parenting styles. Neurobiological studies in bipolar offspring are just beginning to yield findings that may be related to the underlying neuropathophysiology of BD. The future holds promise for longitudinal studies of bipolar offspring incorporating all of these facets, including genetic analyses, to further elucidate the factors involved in the evolution of BD.

Abstract

Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression.To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.Double-blind, 8-week, randomized controlled trial.Eighty-four sites (inpatient and outpatient) in 13 countries. Patients A total of 833 randomized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20. Intervention Patients were randomly assigned to receive placebo (n = 377); olanzapine, 5 to 20 mg/d (n = 370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86).Changes in MADRS total scores using mixed-effects model repeated-measures analyses.During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group (P or =15 subsequently) did not differ among groups (placebo, 6.7% [23/345]; olanzapine, 5.7% [19/335]; and olanzapine-fluoxetine, 6.4% [5/78]). Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea.Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.

Abstract

We wished to characterize temperament of children at high risk for bipolar disorder (BD).We collected data from the Dimensions of Temperament-Revised (DOTS-R) from 53 biological offspring of at least one parent with BD.Overall, our cohort differed from population means for the DOTS-R, having decreased Activity Level-General scores, and increased Approach, and Rhythmicity-Sleep scores. Offspring with psychiatric disorders differed from those without in having decreased Flexibility, Mood, and Task Orientation scores. Temperament profiles for diagnostic categories of BD and attention-deficit/hyperactivity disorder were performed in a descriptive manner.Self- or parent-report of temperament was used rather than clinical observation. Temperament characterization was cross-sectional and retrospective rather than prospective and may overlap with clinical diagnoses.Assessment of temperament may be useful in characterizing bipolar offspring. Decreased flexibility and task orientation, and presence of negative moods may be correlated with development of psychopathology.

Abstract

Based on the mood-stabilizing properties of carbamazepine and valproate, new anticonvulsants have been explored for use in bipolar disorders. One such agent, lamotrigine, has a novel clinical profile in that it may "stabilize mood from below," as it appears to maximally impact depressive symptoms in bipolar disorders. In this paper, we review the mechanisms of action of lamotrigine in an effort to understand the basis of its distinctive clinical use in the management of bipolar disorders as well as its diverse antiseizure effects. We consider lamotrigine mechanisms, emphasizing commonalities and dissociations among actions of lamotrigine, older mood stabilizers, and other anticonvulsants. Although ion channel effects, especially sodium channel blockade, may importantly contribute to antiseizure effects, such actions may be less central to lamotrigine thymoleptic effects. Antiglutamatergic and neuroprotective actions are important candidate mechanisms for lamotrigine psychotropic effects. Lamotrigine has a variable profile in kindling and contingent tolerance experiments and does not appear to have robust gamma-aminobutyric acid or monoaminergic actions. Lamotrigine intracellular signaling effects warrant investigation. Although lamotrigine mechanisms overlap those of other mood-stabilizing anticonvulsants, important dissociations suggest candidate mechanisms, which could contribute to lamotrigine's distinctive psychotropic profile.

Abstract

Offspring of parents with bipolar disorder, by virtue of their high-risk status for developing bipolar disorder, merit an investigation of the efficacy of treatment with mood stabilizers. Behavioral and mood difficulties in this population may represent prodromal forms of bipolar disorder. We studied the efficacy of divalproex in treating child and adolescent bipolar offspring with mood or behavioral disorders who did not yet meet criteria for bipolar I or II disorder.We studied 24 children aged 6-18 years (mean = 11.3 years; 17 boys/7 girls) with at least 1 biological parent with bipolar disorder. Participants were diagnosed by the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia with at least 1 of the following DSM-IV disorders: major depressive disorder, dysthymic disorder, cyclothymic disorder, or attention-deficit/hyperactivity disorder. Subjects all had at least moderate affective symptoms (28-item Hamilton Rating Scale for Depression or Young Mania Rating Scale score > 12). After a 2-week washout period, subjects were treated with divalproex for 12 weeks, titrated to achieve serum levels of 50-120 micro g/mL (mean final dose = 821 mg/day; mean final serum level = 79.0 micro g/mL).One subject discontinued after 2 weeks due to continuation of symptoms. Of the remaining 23 subjects, 18 (78%) were considered responders by primary outcome criteria ("very much improved" or "much improved" on the Clinical Global Impressions-Improvement scale). Divalproex was well tolerated with no discontinuations due to adverse effects.Bipolar offspring with mood or behavioral disorders and at least mild affective symptoms may respond to divalproex treatment. Our study was limited by the open treatment, lack of a placebo group, and the heterogeneous nature of the sample. Controlled studies are warranted in the use of divalproex in symptomatic bipolar offspring.

Abstract

Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex.This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest.Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness.In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.

Abstract

Children of parents with bipolar disorder (bipolar offspring) represent a rich cohort for study with potential for illumination of prodromal forms of bipolar disorder. Due to their high-risk nature, bipolar offspring may present phenomenological, temperamental, and biological clues to early presentations of bipolar disorder. This article reviews the evidence for establishing bipolar offspring as a high-risk cohort, the studies which point to possible prodromal states in bipolar offspring, biological findings in bipolar offspring which may be indicators of even higher risk for bipolar disorder, initial attempts at early intervention in prodromal pediatric bipolar disorder, and implications for future research.

Abstract

Relatively low levels of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may indicate decreased neuronal density or viability. Dorsolateral prefrontal levels of N-acetylaspartate have been reported to be decreased in adults with bipolar disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral prefrontal N-acetylaspartate levels in children with familial bipolar disorder.Subjects were 15 children and adolescents with bipolar disorder, who each had at least one parent with bipolar disorder, and 11 healthy controls. Mean age was 12.6 years for subjects and controls. Subjects were allowed to continue current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used to study 8 cm(3) voxels placed in left and right dorsolateral prefrontal cortex.Bipolar subjects had lower N-acetylaspartate/Creatine ratios only in the right dorsolateral prefrontal cortex (p

Abstract

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age >/= 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, the treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention.

Abstract

Anticonvulsant drugs (ACs) have diverse antiseizure, psychotropic, and biochemical effects. Carbamazepine and valproate have mood-stabilizing actions, benzodiazepines and gabapentin have anxiolytic actions, lamotrigine is useful in rapid cycling and acute treatment and prophylaxis of bipolar depression, and topiramate and zonisamide can yield weight loss. Limited controlled data suggest the carbamazepine keto derivative oxcarbazepine has antimanic effects. A categorical approach to the diverse roles of ACs in bipolar disorders is proposed, using broad categories of ACs, on the basis of their predominant psychotropic profiles. Thus, some ACs have "sedating" profiles that may include sedation, cognitive difficulties, fatigue, weight gain, and possibly antimanic and/or anxiolytic effects. In contrast, some newer ACs have "activating" profiles that may include improved energy, weight loss, and possibly antidepressant and even anxiogenic effects. Still other newer ACs have novel "mixed" profiles, combining sedation and weight loss. A categorical-mechanistic extension of this approach is also presented, with hypotheses that "sedating" profiles might be related to prominent potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, "activating" profiles could be related to prominent attenuation of glutamate excitatory neurotransmission, and for "mixed" profiles, sedation and weight loss might be related to concurrent GABAergic and antiglutamatergic actions, respectively. The categorical approach may have utility as an aid to clinicians in reinforcing the heterogeneity ACs, and recalling psychotropic profiles of individual ACs, but is limited as it fails to address the etiology of the heterogeneity of AC psychotropic effects. The categorical-mechanistic extension strives to address this issue, but requires systematic clinical investigation of more precise relationships between psychotropic profiles and discrete mechanisms of action to assess its merits.

Abstract

Treatment options to relieve the diverse symptoms encountered in patients with bipolar disorders include not only mood stabilizers, but also anxiolytics, new anticonvulsants, antidepressants, and antipsychotics. These agents have widely varying mechanisms of action, which could contribute to the heterogeneity of clinical effects seen in practice. Several of these medications, especially those with anticonvulsant effects, enhance gamma-aminobutyric acid (GABA) inhibitory neurotransmission and/or attenuate glutamate excitatory neurotransmission. We review the efficacy and tolerability of these diverse treatment options in bipolar disorders and explore possible relationships between clinical effects and GABAergic and antiglutamatergic mechanisms of action.

Abstract

To evaluate effects of olanzapine in diverse exacerbations of bipolar disorders.Twenty-five evaluable bipolar disorder [14 bipolar I (BPI), 10 bipolar II (BPII) and one bipolar disorder not otherwise specified (BP NOS)] outpatients received open olanzapine (15 adjunctive, 10 monotherapy). Thirteen had elevated (11 syndromal, two subsyndromal) and 12 depressed (four syndromal, eight subsyndromal) mood symptoms of at least mild severity, with Clinical Global Impression-Severity (CGI-S) scores of at least 3. Only one had psychotic symptoms.With open olanzapine (15 adjunctive, 10 monotherapy), overall symptom severity (CGI-S) as well as mood elevation (Young Mania Rating Scale), depression (Hamilton and Montgomery-Asberg Depression Rating Scales), and anxiety (Hamilton Anxiety Rating Scale), rapidly decreased (significantly by days 2-3). Patients with the greatest baseline severity (CGI-S) had the greatest improvement. Fifteen of 25 (60%) patients responded. Time to consistent response was bimodal, with five early (by 0.5 +/- 0.3 weeks) and 10 late (by 7.0 +/- 1.9 weeks) responders. Early compared with late responders had 51% lower final olanzapine doses. Olanzapine was generally well tolerated, with sedation and weight gain the most common adverse effects.Olanzapine was effective in diverse exacerbations of bipolar disorders. The bimodal distribution of time to response and different final doses are consistent with differential mechanisms mediating early compared with late responses. Controlled studies are warranted to further explore these preliminary observations.

Abstract

We present a fully automated cerebrum segmentation algorithm for full three-dimensional sagittal brain MR images. First, cerebrum segmentation from a midsagittal brain MR image is performed utilizing landmarks, anatomical information, and a connectivity-based threshold segmentation algorithm as previously reported. Recognizing that cerebrum in laterally adjacent slices tends to have similar size and shape, we use the cerebrum segmentation result from the midsagittal brain MR image as a mask to guide cerebrum segmentation in adjacent lateral slices in an iterative fashion. This masking operation yields a masked image (preliminary cerebrum segmentation) for the next lateral slice, which may truncate brain region(s). Truncated regions are restored by first finding end points of their boundaries, by comparing the mask image and masked image boundaries, and then applying a connectivity-based algorithm. The resulting final extracted cerebrum image for this slice is then used as a mask for the next lateral slice. The algorithm yielded satisfactory fully automated cerebrum segmentations in three-dimensional sagittal brain MR images, and had performance superior to conventional edge detection algorithms for segmentation of cerebrum from 3D sagittal brain MR images.

Abstract

The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial.A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures.The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (> or = 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment.The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex.

Abstract

Treatment of bipolar disorders has progressed significantly in the last decade due to advances in basic and clinical research. Much of this progress has centered on the development of a new generation of mood stabilizers-anticonvulsants. Valproic acid (VPA) and carbamazepine (CBZ) have clear mood stabilizing properties, while lamotrigine (LTG), topiramate (TPM), and gabapentin (GBP) have been investigated to varying degrees. We provide an overview of mechanisms of these potentially mood-stabilizing anticonvulsants, review their commonalities and dissociations to the gold standard non-anticonvulsant mood stabilizer lithium. Regulations of the glutamate excitatory neurotransmission and/or gamma aminobutyric acid (GABA) inhibitory neurotransmission are mostly studied mechanisms of anticonvulsants. The divergent effects of these agents indicate that this mode of action represents initial effect of anticonvulsants in regulating mood. Similar to lithium, intracellular mechanisms of anticonvulsants, primarily VPA and CBZ, include regulation of several protein kinase signaling pathways, leading to regulation of gene expression. Common genes that can be regulated by mood stabilizers are more likely to be the final normalizing components in bipolar disorders. Several anticonvulsants, such as VPA, LTG, and TPM, show neuronal protective function, a commonality with recently identified neuroprotective function of lithium, although the meaning of neuroprotection in bipolar disorders remains to be identified. Understanding the mechanisms of anticonvulsant mood stabilizers, integrated with clinical observations, may ultimately provide important new insights into the pathophysiology and treatment of bipolar disorders.

Abstract

We determined clustering of depressive symptoms in a combined group of unipolar and patients with bipolar disorder using Principle Components Analysis of the Beck Depression Inventory. Then, comparing unipolars and bipolars, these symptom clusters were examined for interrelationships, and for relationships to regional cerebral metabolism for glucose measured by positron emission tomography.[18F]-fluoro-deoxyglucose positron emission tomography scans and Beck Depression Inventory administered to 31 unipolars and 27 bipolars, all medication-free, mildly-to-severely depressed. BDI component and total scores were correlated with global cerebral metabolism for glucose, and voxel-by-voxel with cerebral metabolism for glucose corrected for multiple comparisons.In both unipolars and bipolars, the psychomotor-anhedonia symptom cluster correlated with lower absolute metabolism in right insula, claustrum, anteroventral caudate/putamen, and temporal cortex, and with higher normalized metabolism in anterior cingulate. In unipolars, the negative cognitions cluster correlated with lower absolute metabolism bilaterally in frontal poles, and in right dorsolateral frontal cortex and supracallosal cingulate.Psychomotor-anhedonia symptoms in unipolar and bipolar depression appear to have common, largely right-sided neural substrates, and these may be fundamental to the depressive syndrome in bipolars. In unipolars, but not bipolars, negative cognitions are associated with decreased frontal metabolism. Thus, different depressive symptom clusters may have different neural substrates in unipolars, but clusters and their substrates are convergent in bipolars.

Abstract

Normal cerebral glucose metabolism (CMRglc) was assessed with positron emission tomography in 66 healthy adults (28 women, 38 men; mean age 39, range 20--69 years) to determine effects of age, sex and laterality on CMRglc using statistical parametric mapping. Significant age-related decreases in global metabolism (gCMRglc) were noted in the entire sample and in both sexes, as well as widespread and bilateral decreases in cortical absolute regional metabolism (rCMRglc) and more focal anterior paralimbic normalized rCMRglc. However, significant positive correlations of age with normalized rCMRglc were observed in cerebellum, thalamus and occipital areas. Although the declines in gCMRglc and rCMRglc with age did not significantly differ between sexes, men compared with women had significantly lower gCMRglc and widespread decreased cortical and subcortical absolute rCMRglc. In the entire sample, and similarly in both sexes, left greater than right asymmetry was observed in medial frontal gyrus, posterior thalamus, lingual gyrus, cuneus and superior cingulate. The opposite laterality appeared in mesio-anterior cerebellum, and lateral frontal and temporal regions. Few regions showed significant interactions of metabolic laterality with either age or sex. These findings contribute toward a convergence in the literature, and the regression models of CMRglc vs. age serve as a normative database to which patients may be compared.

Abstract

Patients with unipolar depression are most often reported to have decreased regional cerebral glucose metabolism (rCMRglu) in dorsal prefrontal and anterior cingulate cortices compared with healthy control subjects, often correlating inversely with severity of depression.We measured rCMRglu with fluorine-18 deoxyglucose positron emission tomography (PET) in 38 medication-free patients with unipolar depression and 37 healthy control subjects performing an auditory continuous performance task to further investigate potential prefrontal and anterior paralimbic rCMRglu abnormalities in patients attending to this task.Compared with control subjects, the subgroup of patients with Hamilton depression scores of 22 or greater demonstrated decreased absolute rCMRglu in right prefrontal cortex and paralimbic/amygdala regions as well as bilaterally in the insula and temporoparietal cortex (right > left); they also exhibited increased normalized metabolic activity bilaterally in the cerebellum, lingula/cuneus, and brain stem. Severity of depression negatively correlated with absolute rCMRglu in almost the entire extent of the right cingulate cortex as well as bilaterally in prefrontal cortex, insula, basal ganglia, and temporoparietal cortex (right > left).Areas of frontal, cingulate, insula, and temporal cortex appear hypometabolic in association with different components of the severity and course of illness in treatment-resistant unipolar depression.

Abstract

The objective of the current study was to examine possible clinical predictors of positive response to lamotrigine or gabapentin monotherapy in treatment-refractory affectively ill patients.Forty-five patients with treatment refractory bipolar (n = 35) or unipolar (n = 10) affective disorder participated in a clinical study evaluating six weeks of treatment with lamotrigine, gabapentin, or placebo monotherapy given in a double-blind, randomized fashion with two subsequent cross-overs to the other agents. Patients received daily mood ratings and weekly cross-sectional scales. Much or very much improved on the Clinical Global Impression scale modified for bipolar illness was considered a positive response. Degree of response was correlated with a number of baseline demographic and course of illness variables in a univariate analysis and then by linear regression.Response rates to lamotrigine (51%) exceeded those to gabapentin (28%) and placebo (21%). A positive response to lamotrigine monotherapy was associated with a bipolar diagnosis; fewer hospitalizations; fewer prior medication trials; and male gender (of which the latter two variables survived logistic regression). For gabapentin, degree of response correlated with shorter duration of illness; younger age; and lower baseline weight (with the latter two surviving linear regression).In this highly treatment-refractory population, lamotrigine appeared most effective for male patients with fewer prior medication trials. Gabapentin monotherapy, although not better than placebo, appeared most effective in those with younger age and lower baseline weight. These preliminary data in a treatment refractory subgroup may help in the further definition of the range of clinical utility of these widely used anticonvulsants.

Abstract

Management of bipolar disorder has traditionally emphasized the acute treatment of mania. Although acute treatment of mania is a critical aspect of care, this emphasis has tended to overshadow other important phases of bipolar disorder, such as depression, hypomania, and subsyndromal symptoms. We offer a reconceptualization of bipolar disorder that highlights unmet needs and the importance of differential spectra of efficacy. In this reconceptualization, bipolar disorder can be viewed as an aberration of mood, behavior, and cognition from baseline (euthymia). "Below baseline" is characterized by depression and subsyndromal depression. "Above baseline" is characterized by mania, mixed states, hypomania, and subsyndromal mood elevation. In contrast to the treatment options for mania, the options for depression are limited. This new nomenclature emphasizes the need to develop mood stabilizers that possess the ability to stabilize mood "from below baseline," either alone or in combination with other agents. In this article, the treatment options for bipolar disorder, with a focus on depression and rapid cycling, are discussed according to this new conceptualization of management from below and above baseline.

Abstract

Recognition of facial emotion was examined in manic subjects to explore whether aberrant interpersonal interactions are related to impaired perception of social cues.Manic subjects with bipolar I disorder (N=8), euthymic subjects with bipolar I (N=8) or bipolar II (N=8) disorder, and healthy comparison subjects (N=10) matched pictures of faces to the words "fear," "disgust," "anger," "sadness," "surprise," and "happiness."The manic subjects showed worse overall recognition of facial emotion than all other groups. They showed worse recognition of fear and disgust than the healthy subjects. The euthymic bipolar II disorder subjects showed greater fear recognition than the manic and euthymic bipolar I disorder subjects.Impaired perception of facial emotion may contribute to behaviors in mania. Impaired recognition of fear and disgust, with relatively preserved recognition of other basic emotions, contrasts with findings for depression and is consistent with a mood-congruent positive bias.

Abstract

The clinical features of bipolar disorders can be correlated with responses to medications. Patients who respond to lithium, for example, often present differently from those who respond to divalproex or carbamazepine, but the correlations are relatively modest. Brain-imaging tools, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), can relate brain function to clinical features and medication responses. For example, in depression, it appears that prefrontal cortical function is decreased while subcortical anterior paralimbic activity is increased. Preliminary evidence suggests that baseline metabolism increases and decreases in the left insula may be associated with carbamazepine and nimodipine responses, respectively, and that cerebral lithium concentrations may correlate with antimanic effects. Although it is not yet a clinical tool for bipolar disorders, brain imaging provides useful research data to understand the fundamental neurobiology of mood disorders and to more effectively target therapeutics.

Abstract

Mechanisms of action, efficacy spectra, pharmacokinetics, and adverse effects differentiate the mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA). Lithium, which has a low therapeutic index, is excreted through the kidneys, resulting in renally mediated, but not hepatically mediated, drug-drug interactions. CBZ also has a low therapeutic index and is metabolized primarily by a single isoform (CYP3A3/4). It has an active epoxide metabolite, is susceptible to CYP3A3/4 or epoxide hydrolase inhibitors, and is able to induce drug metabolism (both via cytochrome P450 oxidation and conjugation). CBZ thus has multiple problematic drug-drug interactions. In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, and it is less susceptible to pharmacokinetic drug interactions. Still, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of certain medications by displacing them from plasma proteins. The newer anticonvulsants lamotrigine, topiramate, and tiagabine have different, generally less problematic, hepatically mediated drug-drug interactions. Gabapentin, which is renally excreted, lacks hepatic drug-drug interactions, though bioavailability may be reduced at higher doses. Recently approved anticonvulsants, including oxcarbazepine, zonisamide, and levetiracetam, may have improved pharmacokinetic profiles compared to older agents. Novel psychotropic effects of these drugs may also be demonstrated, based on their mechanisms of action and preliminary clinical data.

Abstract

There have been few systematic studies of the treatment of bipolar II depression. While divalproex sodium (DVPX) is effective in acute mania, there are few data on the antidepressant effects of DVPX. Similarly, little is known regarding the use of DVPX administered in a single daily dose.We performed a 12-week open trial of DVPX monotherapy (mean dose 882 mg qhs, mean level 80.7 mug/ml) in nineteen (thirteen women, six men, mean age 29) bipolar II depressed outpatients. Eleven patients (six women, five men) were medication-naive (MN) and eight (seven women, one man) were mood stabilizer-naive (MSN), having had prior trials of antidepressants or stimulants. Mean illness and current depressive episode duration were 15.4 years and 11.8 weeks, respectively. DVPX was given as a single dose each evening starting with 250 mg at bedtime and increased by 250 mg at bedtime every 4 days until symptom relief or adverse effects were noted. Weekly prospective Hamilton Depression, Young Mania and Clinical Global Impression ratings were obtained.DVPX therapy was generally well tolerated. Twelve of nineteen patients (63%) responded (>50% decrease in Hamilton Depression ratings). MN patients compared to MSN patients tended to have a higher response rate (9/11 versus 3/8, P<0.08). Mean Hamilton scores decreased from 22.2 to 9.6 (P<0.0001) in the entire group, from 20.6 to 6.6 (P<0.0003) in MN patients, and from 24.2 to 14.7 (P=0.008) in MSN patients.Single daily dose DVPX monotherapy appeared to be well tolerated and substantially benefited 63% of patients with bipolar II depression. The trend towards a higher rate of antidepressant response to DVPX in MN patients (82%) compared to MSN patients (38%) could be due to a milder form or earlier phase of illness and the lack of prior medication exposure or failures. This uncontrolled open pilot study must be viewed with caution, and randomized double-blind placebo controlled studies of DVPX in bipolar II depression are warranted to confirm the possibility that single daily dose DVPX is an effective, well-tolerated, first-line monotherapy in this population.

Abstract

Previous studies show a state-dependent relationship between depression and post-dexamethasone suppression test (DST) cortisol level, as well as differences in DST response with age and gender.In this study, 74 research in-patients with affective disorders were given the DST on placebo and in a subgroup following treatment with carbamazepine. Depression was evaluated twice daily with the Bunney-Hamburg (BH) rating scale. Data were examined for the total subject population, by gender and by menopausal status in women.A robust positive correlation was observed between depression severity and post-DST cortisol in pre- and postmenopausal females, but not in males. This relationship persisted in women when restudied on a stable dose of carbamazepine (n=42).The pathophysiological implications of this selective positive relationship between severity of depression and post-DST cortisol in women, but not men, should be explored further.

Abstract

The effect of family environment on the development of bipolar disorder (BD) in children is not known. We sought to characterize families with children at high risk for developing BD in order to better understand the contributions of family environment to the development of childhood BD.We collected demographic data and parental ratings on the Family Environment Scale (FES) for 56 children (aged 6-18 years) from 36 families with at least one biological parent with BD. The cohort had previously been psychiatrically diagnosed according to semistructured interviews.Statistical comparisons with normative data indicated that parents' ratings were significantly lower on the FES Cohesion and Organization scales and were significantly higher on the FES Conflict scale. Multivariate analyses of variance indicated that families with both parents having a mood disorder had no significantly different FES scores than families with only one parent with a mood disorder (BD). Diagnostic data indicated that while 54% of the children in the sample had an Axis I disorder and 14% had BD, FES scores did not differ significantly for subjects with or without an Axis I disorder, or with or without BD.Families with a bipolar parent differ from the average family in having less cohesion and organization, and more conflict. Despite this difference, it does not appear that the environment alone of families with a bipolar parent determines the outcome of psychopathology in the children, or that the psychopathology of the children determines the family environment.

Abstract

Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.

Abstract

Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable.Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose.Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency.In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established.

Abstract

We studied the relationship between regional cerebral metabolism and the severity of anxiety in mood disorder patients, controlling for depression severity.Fifty-two medication-free patients with unipolar or bipolar illness underwent positron emission tomography with [(18)F]-fluorodeoxyglucose. Hamilton Depression Rating Scale and Spielberger Anxiety-State Scale scores were obtained for the week of the scan. Analyses were performed on globally normalized images and were corrected for multiple comparisons.After covarying for depression scores, age, and gender, Spielberger Anxiety-State Scale scores correlated directly with regional cerebral metabolism in the right parahippocampal and left anterior cingulate regions, and inversely with metabolism in the cerebellum, left fusiform, left superior temporal, left angular gyrus, and left insula. In contrast, covarying for anxiety scores, age, and gender, Hamilton Depression Rating Scale scores correlated directly with regional cerebral metabolism in the bilateral medial frontal, right anterior cingulate, and right dorsolateral prefrontal cortices.Comorbid anxiety symptoms are associated with specific cerebral metabolic correlates that partially overlap with those in the primary anxiety disorders and differ from those associated with depression severity.

Abstract

Psychosis is a cardinal symptom of schizophrenia, but also occurs in other psychiatric conditions, including mood disorders. In many instances, brain abnormalities in psychotic and mood disorders appear to be on a spectrum, with the most marked changes in schizophrenia, followed by psychotic mood disorders, followed by nonpsychotic mood disorders. Such observations are consistent with the notion that mood disorders and schizophrenia represent a continuum of disease. However, in some instances, cerebral changes with psychosis may be qualitatively different, rather than merely more severe than those seen in mood disorders, more consistent with the theory that they are discrete entities. We review brain imaging studies that have advanced our knowledge of psychosis in mood disorders, with respect to the continuum versus discrete entity hypotheses.

Abstract

To establish prodromal signs of and risk factors for childhood bipolar disorder (BD) by characterizing youths at high risk for BD.Structured diagnostic interviews were performed on 60 biological offspring of at least one parent with BD. Demographics, family histories, and parental history of childhood disruptive behavioral disorders were also assessed.Fifty-one percent of bipolar offspring had a psychiatric disorder, most commonly attention-deficit/hyperactivity disorder (ADHD), major depression or dysthymia, and BD. BD in offspring tended to be associated with earlier parental symptom onset when compared with offspring without a psychiatric diagnosis. Bipolar parents with a history of childhood ADHD were more likely to have children with BD, but not ADHD. Offspring with bilineal risk had increased severity of depressed and irritable mood, lack of mood reactivity, and rejection sensitivity, while severity of grandiosity, euphoric mood, and decreased need for sleep were not preferentially associated with such offspring.Bipolar offspring have high levels of psychopathology. Parental history of early-onset BD and/or childhood ADHD may increase the risk that their offspring will develop BD. Prodromal symptoms of childhood BD may include more subtle presentations of mood regulation difficulties and less presence of classic manic symptoms.

Abstract

We report on three cases of acutely manic prepubertal children diagnosed with bipolar disorder who were treated with olanzapine in addition to their existing mood stabilizer regimens. All three had marked improvement of their manic symptoms within 3-5 days of beginning olanzapine therapy as measured by clinician-rated instruments. Adverse effects included sedation and weight gain. These results suggest that olanzapine may have an antimanic or mood stabilizing effect in acutely manic children with bipolar disorder.

Abstract

N-acetyl aspartate (NAA) is an amino acid present in high concentrations in neurons and is thus a putative neuronal marker. In vivo proton magnetic resonance spectroscopy ((1)H MRS) studies have shown lower NAA concentrations in patients with various neurodegenerative disorders, suggesting decreased neuronal number, size, or function. Dorsolateral prefrontal (DLPF) NAA has not been extensively assessed in bipolar disorder patients, but it could be decreased in view of consistent reports of decreased DLPF cerebral blood flow and metabolism in mood disorders. We measured DLPF NAA in patients with bipolar disorder and healthy control subjects using in vivo (1)H MRS.We obtained ratios of NAA, choline, and myoinositol (mI) to creatine-phosphocreatine (Cr-PCr) in bilateral DLPF 8-mL voxels of 20 bipolar patients (10 Bipolar I, 10 Bipolar II) and 20 age- and gender-matched healthy control subjects using (1)H MRS.DLPF NAA/Cr-PCr ratios were lower on the right hemisphere (p

Abstract

Few studies have approached the subject of polypharmacotherapy systematically. This retrospective review of 178 patients with refractory bipolar disorder or unipolar depression (Research Diagnostic Criteria or DSM-III-R criteria) discharged from the National Institute of Mental Health (NIMH) Biological Psychiatry Branch between 1974 and 1996 was conducted to assess the degree and efficacy of "add-on" pharmacotherapy.Following completion of formal structured blinded research protocols, patients entered a treatment phase (often again on a blind basis) in which all agents available in the community could be utilized. Each patient's retrospective life chart and all prospective double-blind nurse- and self-rated NIMH data were reviewed. The overall degree of improvement at discharge was assessed by rating on the Clinical Global Impressions scale (CGI) as modified for bipolar illness (CGI-BP).A 78% improvement rate (moderate or marked on the CGI) was achieved at the time of discharge. There was a significant relationship between number of medications utilized at discharge as a function of discharge date (r = 0.45, p < .0001). The percentages of patients discharged on treatment with 3 or more medications were 3.3% (1974-1979), 9.3% (1980-1984), 34.9% (1985-1989), and 43.8% (1990-1995). No correlation was found between polypharmacy and age (r = -0.03, p = .66). Patients more recently discharged from the NIMH had an earlier age at illness onset, more lifetime weeks depressed, and a higher rate of rapid cycling than patients in the earlier cohorts.Increasing numbers of medications in more recent NIMH cohorts were required to achieve the same degree of improvement at hospital discharge. More systematic approaches to the complex regimens required for treatment of patients with refractory mood disorder are clearly needed.

Abstract

Positron emission tomography (PET) studies have reported baseline (medication free) differences between mood disorder patients and healthy control subjects, but relatively little is known about relationships between baseline PET scans and treatment responses. Carbamazepine (CBZ) and to a more limited extent nimodipine (NIMO) seem useful in mood disorders. We explored whether baseline regional cerebral glucose metabolism (rCMRglu) could discriminate CBZ and NIMO responders from nonresponders and healthy control subjects.In refractory mood disorder patients, we examined relationships between responses to these drugs, assessed by Clinical Global Impression-Improvement scores, and baseline rCMRglu, determined with fluorine-18 deoxy-glucose and PET.CBZ responders had baseline left insular hyper-metabolism compared to healthy control subjects and nonresponders, whereas nonresponders had widespread (including left insular) hypometabolism. Degree of CBZ response correlated with baseline paralimbic (including insula) and prefrontal hypermetabolism. In responders but not nonresponders, CBZ decreased widespread metabolism, with the degree of decrease in left insula correlating with response. In contrast, NIMO responders but not nonresponders had baseline widespread (including left insular) hypometabolism. Left prefrontal and left insular baseline hypometabolism, but not metabolic changes with treatment correlated with degree of NIMO response.These data suggest that baseline anterior paralimbic and prefrontal hypermetabolism may be associated with CBZ response, and hypometabolism with NIMO response. Based on these preliminary data, further exploration of relationships between baseline PET scans and treatment responses is indicated.

Abstract

Antiepileptic drugs (AEDs) have various mechanisms of actions and therefore have diverse anticonvulsant, psychiatric, and adverse effect profiles. Two global categories of AEDs are identified on the basis of their predominant psychotropic profiles. One group has "sedating" effects in association with fatigue, cognitive slowing, and weight gain, as well as possible anxiolytic and antimanic effects. These actions may be related to a predominance of potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission induced by drugs such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. The other group is associated with predominant attenuation of glutamate excitatory neurotransmission and has "activating" effects, with activation, weight loss, and possibly anxiogenic and antidepressant effects. This group includes agents such as felbamate and lamotrigine. Agents such as topiramate, with both GABAergic and antiglutamatergic actions, may have "mixed" profiles. Mechanisms of actions, activity in animal models of anxiety and depression, and clinical psychotropic effects of AEDs in psychiatric and epilepsy patients are reviewed in relationship to this proposed categorization. These considerations suggest the testable hypothesis that better psychiatric outcomes in seizure disorder patients could be achieved by treating patients with baseline "activated" profiles (insomnia, agitation, anxiety, racing thoughts, weight loss) with "sedating" predominantly GABAergic drugs, and conversely those with baseline "sedated" or anergic profiles (hypersomnia, fatigue, apathy, depression, sluggish cognition, weight gain) with "activating" predominantly antiglutamatergic agents. Systematic clinical investigation of more precise relationships of discrete mechanisms of actions to psychotropic profiles of AEDs is needed to assess the utility of this general proposition and define exceptions to this broad principle.

Abstract

Several studies have demonstrated that transient self-induced sadness activates anterior paralimbic structures. To further examine the specificity of these findings and the neural substrates involved in anger and anxiety, we studied the neural correlates of the induction of anxiety and anger in healthy adults.We used H2(15)O and positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in 16 healthy adults during the induction of transient anxiety, anger, and neutral emotions. Subjects achieved differential emotions by recalling prior life events while viewing affect-appropriate faces.Both the anxiety and anger conditions were associated with increased normalized rCBF in left inferior frontal and left temporal pole regions and decreased rCBF in right posterior temporal/parietal and right superior frontal cortex, compared to the neutral induction. Additionally, compared to neutral induction, anxiety was associated with increased rCBF in the left anterior cingulate and cuneus and decreased rCBF in right medial frontal cortex, while the anger induction was uniquely associated with increased rCBF in right temporal pole and thalamus.Self-generated transient states of anxiety and anger are associated with both overlapping and distinct regional brain activity patterns and provide a template for further dissection of specific components of normal and pathologic emotions.

Abstract

1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions. 2. CBZ has multiple problematic drug-drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug-drug interactions, while the renally excreted gabapentin lacks hepatic drug-drug interactions but may have reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects.

Abstract

While the antidepressants venlafaxine and bupropion are known to have different neurochemical profiles in vitro, their effects on human cerebral metabolism in vivo have not been directly compared.Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), serotonin, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined in 14 never-hospitalized outpatients with unipolar depression and 10 age-similar healthy controls. Patients received a baseline lumbar puncture (LP), which was repeated after at least 6 weeks of randomized monotherapy with either venlafaxine or bupropion, while controls received only a baseline LP.Patients (n = 9) receiving venlafaxine showed a significant decrease (42%) in their CSF 5-HIAA concentrations after treatment, but no change in other CSF measures. In contrast, patients receiving bupropion (n = 8) showed no change in CSF measures compared to pretreatment values.While the mechanism for this differential effect of venlafaxine remains to be determined, the current study provides confirmation of the different aminergic effects of venlafaxine and bupropion.

Abstract

Lithium (Li) and gabapentin are both exclusively eliminated by renal excretion. When used in combination, a competitive drug-drug interaction could possibly alter Li renal excretion with important clinical implications considering the rather narrow therapeutic index of Li. This study examined the single-dose pharmacokinetic profiles of Li in 13 patients receiving placebo and then steady-state gabapentin (mean daily dose: 3,646.15 mg). During both phases, a single 600-mg dose of Li was orally administered with serial Li levels obtained at time zero and at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours. The pharmacokinetic parameters assessed were the following: area under the concentration time curve (AUC) for Li, maximal concentration of Li (Li Cmax), and time to reach peak Li concentration (Li Tmax). For patients receiving gabapentin, the mean Li AUC at 72 hours was 9.91+/-3.54 mmol x hr/mL and did not differ significantly from the mean Li AUC of 10.19+/-2.89 mmol x hr/mL for patients receiving placebo. The mean Li Cmax was 0.69+/-0.13 mmol/L for gabapentin patients and did not differ from the mean Li Cmax of 0.72+/-0.15 mmol/L for placebo patients. The mean serum Li Tmax was 1.38+/-0.62 hours for gabapentin patients and did not differ significantly from the mean serum Li Tmax of 1.5+/-0.91 hours for placebo patients. These data indicate that gabapentin treatment at this high therapeutic dose does not cause clinically significant alterations in short-term Li pharmacokinetics in patients with normal renal function. These preliminary data warrant further controlled study in a larger, more heterogenous patient sample and a longer duration of assessment, but they do suggest that these two medications may be administered in combination for the management of bipolar disorder.

Abstract

Of 30 patients with treatment-refractory affective illness, 10 showed a moderate to marked response to blind nimodipine monotherapy compared with placebo on the Clinical Global Impressions Scale. Fourteen inadequately responsive patients (3 unipolar [UP], 11 bipolar [BP]) were treated with the blind addition of carbamazepine. Carbamazepine augmentation of nimodipine converted four (29%) of the partial responders to more robust responders. Patients who showed an excellent response to the nimodipine-carbamazepine combination included individual patients with patterns of rapid cycling, ultradian cycling, UP recurrent brief depression, and one with BP type II depression. When verapamil was blindly substituted for nimodipine, two BP patients failed to maintain improvement but responded again to nimodipine and remained well with a blind transition to another dihydropyridine L-type calcium channel blocker (CCB), isradipine. Mechanistic implications of the response to the dihydropyridine L-type CCB nimodipine alone and in combination with carbamazepine are discussed.

Abstract

In this paper, we propose an algorithm for automated segmentation of midsagittal brain MR images. First, we apply thresholding to obtain binary images. From the binary images, we locate some landmarks. Based on the landmarks and anatomical information, we preprocess the binary images, which substantially simplifies the subsequent operations. To separate regions what are incorrectly merged after this initial segmentation, a new connectivity-based threshold algorithm is proposed. Assuming that some prior information about the general shape and location of objects is available, the algorithm finds a boundary between two regions using the path connection algorithm and changing the threshold adaptively. In order to test the robustness of the proposed algorithm we applied the algorithm to 120 midsagittal brain images and obtained satisfactory results.

Abstract

Traditional neuroleptics are often utilized clinically for the management of bipolar disorder. Although effective as antimanic agents, their mood stabilizing properties are less clear. Additionally, their acute clinical side effect profile and long term risk of tardive dyskinesia, particularly in mood disorder patients, portend significant liability. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder focusing on clozapine as the prototypical agent. Although, preclinical research and clinical experience suggest that the atypical antipsychotics are distinctly different from typical antipsychotics, they themselves are heterogeneous in profiles of neuropharmacology, clinical efficacy, and tolerability. The early clinical experience of clozapine as a potential mood stabilizer suggests greater antimanic than antidepressant properties. Conversely, very preliminary clinical experience with risperidone suggests greater antidepressant than antimanic properties and some liability for triggering or exacerbating mania. Olanzapine and sertindole are under investigation in psychotic mood disorders. The foregoing agents and future drugs with atypical neuroleptic properties should come to play an increasingly important role, compared to the older classical neuroleptics, in the acute and long term management of bipolar disorder.

Abstract

Acute transient antidepressant effects of sleep deprivation are consistently observed in 50% of depressed patients, but the mechanisms of these, at times, dramatic improvements in mood have not been adequately elucidated. Some, but not all, studies suggest a relationship to increased thyroid-stimulating hormone (TSH) secretion.TSH and other thyroid indices were measured at 8:00 AM after a baseline night's sleep and at 8:00 AM following a night of total sleep deprivation (S.D.) in 34 medication-free, affective disorder patients assessed with Hamilton, Beck, and Bunney-Hamburg depression ratings as well as two hourly self-ratings on a visual analog scale.Compared with baseline, S.D. induced highly significant increases in TSH, levothyroxine, free levothyroxine, and triiodothyronine. The 12 S.D. responders tended to have greater TSH increases than the 15 nonresponders (p < .10). The change in Beck depression ratings significantly correlated with the change in TSH (r = -.40, p = .0496, n = 24).These data are consistent with several other reports of a significant relationship between degree of antidepressant response to S.D. and increases in TSH measured at 8:00 AM near their usual nadir. Acute removal of the sleep-related break on the hypothalamic-pituitary-thyroid axis remains a promising candidate for the mechanism of sleep deprivation-induced improvement in mood in depressed patients.

Abstract

This study investigated psychosensory symptoms and their relationship to retrospective and prospective courses of illness, as well as therapeutic outcomes, in patients with bipolar disorder. Using the Silberman-Post Psychosensory Rating Scale (SP-PSRS), psychosensory symptoms were assessed in 51 patients who met Diagnostic and Statistical Manual, 3rd Edition-Revised (DSM-III-R) criteria for bipolar disorder and in 39 healthy, normal controls. Patients with bipolar disorder were enrolled in a 3-year, double-blind, randomized study comparing the prophylactic efficacy of lithium or carbamazepine in the first year, a crossover to the other drug in the second year, and the combination of both medications in the third year. Psychosensory scores from patients with bipolar disorder were compared with scores from healthy controls and with a variety of retrospective and prospective course of illness and treatment variables. Psychosensory symptoms occurred frequently in patients with bipolar I and II disorders, but were rare in healthy controls. When depressed, patients with bipolar II disorder (n = 23) reported more psychosensory symptoms when compared to patients with bipolar I disorder (n = 28), and those with a history of rapid cycling (n = 29) reported more psychosensory symptoms when compared to patients without a history of rapid cycling (n = 21). Psychosensory symptoms were not related to response to carbamazepine, lithium, or the combination of both drugs. Although the presence of psychosensory symptoms is associated with some bipolar subtypes (patients with bipolar II disorder and patients with a history of rapid cycling), they do not appear to predict treatment response. Further studies are needed to assess the pathophysiologic implications of the presence of psychosensory symptoms and their potential implications, if any, for directing therapeutics.

Abstract

Therapeutic effects of the tripeptide protirelin (thyrotropin-releasing hormone) have been postulated in the affective disorders, but direct assessment in humans has been hindered by poor blood-brain barrier permeability.Eight medication-free inpatients with refractory depression received 500 micrograms of protirelin via a lumbar intrathecal injection and an identical sham lumbar puncture procedure, separated by 1 week, in a double-blind crossover design.Five of eight patients responded to intrathecal protirelin, defined as a 50% or greater reduction in an abbreviated Hamilton Rating Scale for Depression score. Suicidality also was reduced significantly (P < .05). Responses were rapid and clinically robust, but short-lived.Administration of protirelin by an intrathecal route induced a rapid improvement in mood and suicidality in these refractory depressed patients, supporting the hypothesis that thyrotropin-releasing hormone could be a positive modulator of mood.

Abstract

The author's goal was to investigate relationships between peripheral thyroid hormone levels and cerebral blood flow (CBF) and cerebral glucose metabolism in affectively ill patients.Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F] fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism.Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between T3, T4, or free T4 and global or regional CBF and cerebral glucose metabolism.These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations.

Abstract

A significant amount of preclinical and human data indicate that thyrotropin-releasing hormone (TRH) has antidepressant effects. Although early studies showing these effects using intravenous TRH were not consistently replicated, it has been suggested that this could be explained by its poor blood-brain barrier penetration. For this reason we compared the antidepressant effect of intrathecal and intravenous TRH administered in a double-blind design to 2 treatment-refractory patients with bipolar II disorder. Each experienced a robust antidepressant response by both routes; subsequent open trials of intravenous TRH also were effective until apparent tolerance developed. Intrathecal TRH was readministered and both subjects again experienced robust antidepressant responses. These preliminary data suggest a differential mechanism of tolerance to the two routes of administration and raise the possibility that a subgroup of patients may be responsive to the antidepressant effects of TRH independent of its route of administration.

Abstract

Functional neuroimaging studies have found abnormal anterior cingulate activity in depressed subjects, and other studies have shown that the cingulate gyrus becomes active in healthy subjects during interference tasks. The authors hypothesized that subjects with mood disorder might show blunted cingulate activation during the standard Stroop interference task or during a modified version involving sadness-laden words. In contrast to 11 age- and sex-matched healthy control subjects who activated the left cingulate during the standard Stroop, 11 mood-disordered subjects activated the right anterior cingulate gyrus only slightly and instead showed increased activity in the left dorsolateral prefrontal and visual cortex. This study supports theories of blunted limbic and paralimbic activation and abnormal cingulate activity in depression and adds to the growing knowledge of the functional neuroanatomy of depression.

Abstract

With the increasing recognition of lithium's inadequacy as an acute and prophylactic treatment for many patients and subtypes of bipolar illness, the search for alternative agents has centered around the mood stabilizing anticonvulsants carbamazepine and valproate. In many instances, these drugs are effective alone or in combination with lithium in those patients less responsive to lithium monotherapy, including those with greater numbers of prior episodes, rapid-cycling, dysphoric mania, co-morbid substance abuse or other associated medical problems, and patients without a family history of bipolar illness in first-degree relatives. Nineteen double-blind studies utilizing a variety of designs suggest that carbamazepine, or its keto-congener oxcarbazepine, is effective in acute mania; six controlled studies report evidence of the efficacy of valproate in the treatment of acute mania as well. Fourteen controlled or partially controlled studies of prophylaxis suggest carbamazepine is also effective in preventing both manic and depressive episodes. valproate prophylaxis data, although based entirely on uncontrolled studies, appear equally promising. Thus, both drugs are widely used and are now recognized as major therapeutic tools for lithium-nonresponsive bipolar illness. The high-potency anticonvulsant benzodiazepines, clonazepam and lorazepam, are used adjunctively with lithium or the anticonvulsant mood stabilizers as substitutes or alternatives for neuroleptics in the treatment of manic breakthroughs. Preliminary controlled clinical trials suggest that the calcium channel blockers may have antimanic or mood-stabilizing effects in a subgroup of patients. A new series of anticonvulsants has just been FDA-approved and warrant clinical trials to determine their efficacy in acute and long-term treatment of mania and depression. Systematic exploration of the optimal use of lithium and the mood-stabilizing anticonvulsants alone and in combination, as well as with adjunctive antidepressants, is now required so that more definitive treatment recommendations for different types and stages of bipolar illness can be more strongly evidence based.

Abstract

Men, compared to women, are less likely to experience mood disorders. We wondered if gender differences exist in the ability to self-induce transient sadness and happiness, and in regional cerebral blood flow (rCBF) either at rest or during transient emotions. Ten adult men and 10 age-matched women, all healthy and never mentally ill, were scanned using H2(15)O positron emission tomography at rest and during happy, sad, and neutral states self-induced by recalling affect-appropriate life events and looking at happy, sad, or neutral human faces. At rest, women had decreased temporal and prefrontal cortex rCBF, and increased brainstem rCBF. There were no significant between-group differences in difficulty, effort required, or the degree of happiness or sadness induced. Women activated a significantly wider portion of their limbic system than did men during transient sadness, despite similar self-reported changes in mood. These findings may aid in understanding gender differences with respect to emotion and mood.

Abstract

Remembering the myriad of psychotropic drug interactions is extremely difficult. Nevertheless, by applying a systematic approach, the clinician can often predict the occurrence and time course of such interactions. Several factors must be considered when assessing the potential consequences. Drug-related factors that increase the risk for clinically significant interactions include a low therapeutic index or narrow therapeutic window, a multiplicity of pharmacological actions, and inhibition or inducement of cytochrome P450 enzymes. Next, patient-related factors that can increase the risk for significant drug interactions should be considered. These include genetically based variations in drug-metabolizing capacity, as well as advanced age, underlying medical illness, and comorbid substance abuse. Finally, the literature should be carefully reviewed to as-certain the potential clinical relevance of available data. If a clinically significant drug interaction appears likely to occur, the patient's clinical status should be followed closely; therapeutic drug monitoring should be used if applicable and dosage adjustments made accordingly. Rational polypharmacy requires an understanding of the pharmacological principles governing drug interactions and a knowledge of the factors that increase the likelihood of clinically significant variations in drug action. This will allow the clinician to maximize beneficial effects while minimizing the risk of adverse events.

Abstract

Defects in expressing or understanding the affective or emotional tone of speech (aprosodias) have been associated with right hemisphere dysfunction, while defects of propositional language have been linked to left hemisphere disease. The brain regions involved in recognition of emotional prosody in healthy subjects is less clear.To investigate the brain regions involved in understanding emotional prosody and to determine whether these differ from those involved in understanding emotion based on propositional content.We studied 13 healthy subjects using water labeled with radioactive oxygen 15 and positron emission tomography while they listened to 3 similar sets of spoken English sentences. In different tasks, their responses were based on the emotional propositional content, on the emotional intonation of the sentence (prosody), or on their ability to repeat the second word in the sentence (control).Understanding propositional content activated the prefrontal cortex bilaterally, on the left more than on the right. In contrast, responding to the emotional prosody activated the right prefrontal cortex.Neurologically healthy subjects activate right hemisphere regions during emotional prosody recognition.

Abstract

The objective of this study was to assess the psychiatric effects of the antiepileptic drug (AED) felbamate (FBM) in patients with epilepsy. FBM is a new AED with a novel putative (antiglutaminergic) mechanism. Older AEDs such as carbamazepine and valproate have psychotropic properties, but the psychiatric effects of FBM and other new antiglutamatergic AEDs remain to be determined. Thirty inpatients with refractory epilepsy were openly tapered off all AEDs in conjunction with intensive presurgical monitoring prior to a two week randomized double-blind parallel trial of FBM monotherapy versus placebo, followed by open FBM therapy. Psychopathology was rated with weekly psychiatric rating scales. Anxiety, depression and seizures increased significantly with AED discontinuation. Acute blind FBM monotherapy yielded antiepileptic and stimulant-like effects (insomnia, anorexia, and anxiety), but failed to influence AED withdrawal-emergent psychopathology. Restarting original AEDs resolved such pathology in FBM drop outs. Chronic open FBM also had stimulant-like effects, with half of the patients displaying psychiatric deterioration and the other half modest improvement compared to baseline therapies. Baseline insomnia and anxiety may be markers for poorer psychiatric responses to chronic open FBM. FBM had stimulant-like effects, lacked anxiolytic effects, and failed to attenuate AED withdrawal-emergent psychopathology. Baseline insomnia or anxiety may predict poorer psychiatric responses to FBM. Further studies are required to assess whether the novel psychiatric effects observed with FBM also occur with other new antiglutamatergic AEDs.

Abstract

Bipolar affective illness represents a syndrome not readily treated by single agents. Approximately 50% of patients are inadequately responsive to lithium and the majority of patients require supplemental antidepressants, antimanic, antipsychotic or hypnotic medications. These traditional adjunctive medications are associated with potential problems. Antidepressants may precipitate mania (at a rate about double that of placebo) or cause cycle acceleration. Neuroleptics may be associated with either more profound or longer depressive phases, and clearly increase the risk of tardive dyskinesia, to which bipolar patients appear particularly predisposed. Moreover, there are subgroups of patients who are known to be poorly responsive to lithium. These include patients with rapid cycling, dysphoric mania, co-morbid drug or alcohol abuse, a pattern of depression-mania-well interval (D-M-I as opposed to the M-D-I pattern), and patients without a family history of bipolar illness in first-degree relatives. There is increasing recognition that the anticonvulsants carbamazepine and valproate are effective alternatives or adjuncts to lithium in the acute and long-term treatment of bipolar illness. Ideally, one would want to assess whether patients who were unresponsive to lithium were responsive to an anticonvulsant alone prior to utilizing lithium in addition to anticonvulsant combination therapy. However, from the clinical perspective, it is often more expedient to use an anticonvulsant adjunctively to lithium to assess the efficacy of this combination and establish mood stabilization. When lithium is not discontinued, the increased morbidity during lithium withdrawal also would not occur and would not confound the evaluation of the new agent. We suggest the initial use of acute adjuncts to lithium with the anticonvulsants carbamazepine or valproate (instead of neuroleptics) so that their efficacy can be assessed in the individual's acute episode, with the likelihood of a positive response in longer-term prophylaxis. Hypnotic benzodiazepines with anticonvulsant properties, such as clonazepam or lorazepam, are often used to help to induce sleep in escalating bipolar patients, and may be useful adjuncts as well. Patients who were inadequately responsive to either carbamazepine or valproate alone may be responsive to the anticonvulsant combination. In a similar fashion, one can also utilize several mood-stabilizing drugs (lithium and an anticonvulsant such as carbamazepine or valproate) in the treatment of depressive breakthroughs, and then augment this combination (if necessary) with a catecholamine-active antidepressant such as bupropion or a serotonin-selective reuptake inhibitor (SSRI) such as fluoxetine, paroxetine, sertraline or if necessary a monoamine oxidase inhibitor (MAOI). Once the patient has responded to a combination of drugs, it becomes problematic to decide whether the last agent added was the crucial ingredient in helping the patient achieve remission or that remission might have occurred with this agent alone. A conservative approach would have merit in patients who are finally stabilized on complex polypharmacy regimens only after many years of sequential trials; in this instance, the potential risk of re-exacerbating the illness with a taper of one of the drugs in the regimen. Rational polypharmacy should thus be implemented with careful delineation of the prior course of illness (typically using life chart methodology) and targeted treatment outcomes titrated against side effects, using sequential clinical trials in individual patients who have not adequately responded to monotherapy. In this fashion, it is hoped that pharmacodynamic differences among agents can be maximized and pharmacokinetic and side effects minimized.

Abstract

Recent advances in molecular pharmacology have allowed the characterization of the specific isoforms that mediate the metabolism of various medications. This information can be integrated with older clinical observations to begin to develop specific mechanistic and predictive models of psychotropic drug interactions. The polymorphic cytochrome P450 2D6 has gained much attention, because competition for this isoform is responsible for serotonin reuptake inhibitor-induced increases in tricyclic antidepressant concentrations in plasma. However, the cytochrome P450 3A subfamily and the 3A3 and 3A4 isoforms (CYP3A3/4) in particular are becoming increasingly important in psychopharmacology as a result of their central involvement in the metabolism of a wide range of steroids and medications, including antidepressants, benzodiazepines, calcium channel blockers, and carbamazepine. The inhibition of CYP3A3/4 by medications such as certain newer antidepressants, calcium channel blockers, and antibiotics can increase the concentrations of CYP3A3/4 substrates, yielding toxicity. The induction of CYP3A3/4 by medications such as carbamazepine can decrease the concentrations of CYP3A3/4 substrates, yielding inefficiency. Thus, knowledge of the substrates, inhibitors, and inducers of CYP3A3/ and other cytochrome P450 isoforms may help clinicians to anticipate and avoid pharmacokinetic drug interactions and improve rational prescribing practices.

Abstract

We studied the effect of felbamate (FBM) monotherapy on seizure rate in patients with partial and secondarily generalized seizures undergoing presurgical monitoring at a single site. The study design was a double-blind placebo-controlled parallel monotherapy trial. Forty patients whose seizures had not been controlled by standard antiepileptic drugs (AEDs) were randomized. Seizure type was confirmed by video-EEG monitoring. All baseline AEDs were discontinued, and patients were drug-free for 5.3 +/- 2.4 days before randomization to FBM or placebo. After a 4-day titration, seizures were counted for 14 days. Patients receiving FBM had significantly lower seizure rates, whether all randomized patients, patients who survived titration, or study completers were compared. Eight of 19 placebo patients randomized to placebo, as compared with 13 of 21 receiving FBM, completed the 18-day study. Two FBM patients dropped out due to seizures, and 6 dropped out due to side effects, including anxiety, difficulty sleeping, abdominal discomfort, acute psychosis, and orobuccal dyskinesias. Ten placebo patients met the criteria for premature discontinuation owing to seizures, and 1 hd an episode of panic. There was no evidence of hepatic or hematologic toxicity. FBM reduces seizure frequency in patients with localization-related epilepsy.

Abstract

Converging evidence points to hypofunction of the left prefrontal cortex in depression. Repetitive transcranial magnetic stimulation (rTMS) activates neurons near the surface of the brain. We questioned whether daily left prefrontal rTMS might improve mood in depressed subjects and report a pilot study of such treatment in six highly medication-resistant depressed inpatients. Depression scores significantly improved for the group as a whole (Hamilton Depression Scores decreased from 23.8 +/- 4.2 (s.d.) at baseline to 17.5 +/- 8.4 after treatment; t = 3.03, 5DF, p = 0.02, two-tailed paired t-test). Two subjects showed robust mood improvement which occurred progressively over the course of several weeks. In one subject, depression symptoms completely remitted for the first time in 3 years. Daily left prefrontal rTMS appears to be safe, well tolerated and may alleviate depression.

Abstract

Bupropion (BUP) may be less likely than other antidepressants to cause switches into mania and rapid cycling, suggesting utility in bipolar disorder. The combination of BUP with the mood-stabilizing anticonvulsants carbamazepine (CBZ) or valproate (VPA) is a strategy that might further lessen the risk of mania. CBZ induces, and to a lesser extent VPA inhibits the hepatic metabolism of various medications, but their effects on BUP have not been previously studied. Inpatients with mood disorders had pharmacokinetic profiles of BUP and metabolites assessed after single, oral, 150-mg doses of BUP while receiving placebo (N = 17) or during chronic blind CBZ (N = 12) or VPA (N = 5) monotherapy. CBZ but not VPA therapy decreased BUP peak concentrations (Cmax) by 87% (p < 0.0001) and 24-h area under the curve (AUC) by 90% (p < 0.0001), threohydrobupropion Cmax by 81% (p <0.0009) and AUC by 86% (p < 0.002), and erythropydrobupropion Cmax by 86% (p < 0.05) and AUC by 96% (p < 0.05). CBZ increased hydroxybupropion (H-BUP) Cmax by 71% (p < 0.007) and AUC by 50% (p < 0.09) and H-BUP AUC by 94% (p < 0.02). Thus, CBZ markedly decreased BUP and increased H-BUP concentrations, whereas VPA did not affect BUP but increased H-BUP concentrations. Further studies are required to determine how these differential effects of CBZ and VPA on BUP pharmacokinetics influence the tolerability and efficacy of combination therapies with these agents.

Abstract

Depression is often resistant to treatment with mood stabilizers. The antidepressant effects of carbamazepine can be potentiated by lithium supplementation, but some patients fail to respond to the combination. Although monoamine oxidase inhibitors (MAOIs) appear useful in atypical and bipolar depressions, concerns have been raised regarding safety and pharmacokinetic interactions when they are combined with carbamazepine.Ten inpatients (7 bipolar, 3 unipolar) with refractory DSM-III-R major depression, also resistant to double-blind treatment with carbamazepine, plus lithium augmentation in 8, received double-blind MAOI augmentation (phenelzine in 4, tranylcypromine in 6).All 10 patients tolerated the addition of an MAOI well, and mean self-rated side effect scores did not change significantly. Four of 10 patients improved substantially and became euthymic, allowing discharge from hospital on the carbamazepine +/- lithium plus MAOI combination. These 4 patients improved in spite of prior inadequate responses to the same MAOI without carbamazepine and carbamazepine without an MAOI.This preliminary evidence suggests that the addition of MAOIs to carbamazepine +/- lithium may be well tolerated, may not affect carbamazepine and lithium pharmacokinetics, and may provide relief of refractory depressive symptoms in some patients. Further studies are needed to establish the safety and efficacy of combining carbamazepine with MAOIs.

Abstract

Previous independent EEG and PET studies suggest that administration of intravenous procaine hydrochloride selectively activates limbic brain structures. To further elucidate procaine's effects and explore the relationship between quantitative EEG (qEEG) and regional cerebral blood flow (rCBF), we simultaneously recorded qEEG and sampled rCBF using O-15 water PET in 20 healthy volunteers during single-blind injections of saline (baseline condition) followed by intravenous procaine (1.84 mg/kg). After thorough screening of EEG records, a subgroup of 7 subjects with EEG data relatively free of both muscle and movement artifacts was selected for analysis. Quantitative spectral EEG data from right occipital and temporal leads were then correlated with each subject's PET rCBF values on a pixel by pixel basis, both at baseline and after procaine. The most striking finding was that the increases in occipital and temporal omega activity from baseline to procaine positively correlated with rCBF increases in the amygdala and its efferents (p < .05), in a pattern very similar to the rCBF increases seen after procaine administration. This suggests that omega activity may reflect activation of deeper brain limbic structures. Also, the convergence of EEG and PET data further supports procaine's selective limbic activation.

Abstract

The specific brain regions involved in the normal emotional states of transient sadness or happiness are poorly understood. The authors therefore sought to determine if H2(15)O positron emission tomography (PET) might demonstrate changes in regional cerebral blood flow (rCBF) associated with transient sadness or happiness in healthy adult women.Eleven healthy and never mentally ill adult women were scanned, by using PET and H2(15)O, during happy, sad, and neutral states induced by recalling affect-appropriate life events and looking at happy, sad, or neutral human faces.Compared to the neutral condition, transient sadness significantly activated bilateral limbic and paralimbic structures (cingulate, medial prefrontal, and mesial temporal cortex), as well as brainstem, thalamus, and caudate/putamen. In contrast, transient happiness had no areas of significantly increased activity but was associated with significant and widespread reductions in cortical rCBF, especially in the right prefrontal and bilateral temporal-parietal regions.Transient sadness and happiness in healthy volunteer women are accompanied by significant changes in regional brain activity in the limbic system, as well as other brain regions. Transient sadness and happiness affect different brain regions in divergent directions and are not merely opposite activity in identical brain regions. These findings have implications for understanding the neural substrates of both normal and pathological emotion.

Abstract

We prospectively investigated psychopathology in 32 epilepsy inpatients openly withdrawn from all antiepileptic drugs (AEDs) prior to entering a controlled trial of an investigational AED. Psychiatric ratings and seizures increased significantly with AED discontinuation. Anxiety and depression were the most prominent symptoms. Thirty-eight percent of patients developed moderate-to-severe psychopathology, and 28% dropped out of the study at various stages due to psychiatric symptoms. In 22 patients openly restarted on AEDs, psychiatric ratings returned to baseline within 2 weeks. Increases in partial seizures were weakly related to emergent anxiety and depression. Increases in generalized seizures were related to increases in global impairment but not to increases in specific psychopathology. AED withdrawal-emergent psychopathology was not fully explained by increases in seizures, demographic factors, or psychiatric history and may be partially due to pharmacodynamic effects following drug discontinuation.

Abstract

We report the initial results of the first controlled double-blind trial of nimodipine, a calcium channel antagonist, in the acute and prophylactic treatment of patients with treatment-refractory affective dysregulation. Active drug nimodipine (A) was substituted for placebo (B) in 12 patients. Patients were studied in a B-A-B design, with 3 of the 12 patients rechallenged with active drug in a B-A-B-A design (patients 9, 10, and 11). Five of the nine patients who completed the drug trial responded. One of three patients suffering from ultra-ultra-rapid (ultradian) cycling bipolar II disorder (patient 6) showed an essentially complete response; the other two ultradian patients (patients 4 and 9) showed evidence of a partial response on manic and depressive oscillations, one of which was confirmed in a B-A-B-A design. Only one of five less rapidly, but continuously cycling patients showed an excellent response (patient 10), and this was confirmed in a B-A-B-A design. The one patient who had recurrent brief depression (patient 11) showed a complete resolution of severe depressive recurrences, with response re-confirmed in an extended prophylactic trial with a B-A-B-A design. In the eight patients who completed self-ratings, nimodipine was associated with a significant reduction in the magnitude of mood fluctuations compared with the baseline placebo condition. Further clinical study of nimodipine, a calcium channel blocker with a unique profile of behavioral and anticonvulsant properties, appears warranted in patients with treatment-refractory affective illness characterized by recurrent brief depression and ultradian cycling.

Abstract

Single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies are yielding a picture of clinical depression as a disorder associated with dysfunction in specific brain regions. These data support the view of depression as a disease of the brain in general and of the frontal and temporal lobes in particular. Frontal lobe hypometabolism is emerging as a common final pathway for most types of primary and secondary depression, regardless of the original cause. The severity of depression is often related to the degree of frontal hypometabolism, and preliminary studies indicate that the hypometabolism normalizes after treatment in concert with the patient's improved mood. Primary depression also is associated with abnormal activation of key brain areas, including discrete aspects of the frontal and temporal lobes, the amygdala, and the cingulate gyrus. Several areas of research are currently under way using SPECT or PET to explore further the neuroanatomy of depression.

Abstract

Three patients with treatment-resistant rapidly cycling bipolar disorder were studied with multiple sleep deprivations (SD) during several depressive episodes to assess the effect of phase or duration of a depressive episode on SD response. There was little response to SD early in a depressive episode, but responses were often robust late in an episode, sometimes triggering its termination. In 2 subjects, the duration of antidepressant response to SD increased linearly as time into episode increased. Neither the number of SD given in an episode nor the medication status of the patients appeared to account for the observed increases in antidepressant response. These results suggest that the neurobiological substrates underlying depression may change over the course of an episode, resulting in an increased responsivity to sleep deprivation later compared with earlier in the course of an episode in rapidly cycling patients. The generalizability of these findings to unipolar patients remains to be explored.

Abstract

There is increasing recognition that lithium is inadequate in the treatment of up to 50% of bipolar patients. In addition to subgroups that are nonresponsive from the outset, loss of efficacy (tolerance) and discontinuation-induced refractoriness have recently been observed. The anticonvulsants carbamazepine and valproate are effective alternative or adjunctive treatments, but tolerance can also occur during their long-term prophylactic use. New treatment algorithms for this loss of efficacy, including combination therapies, require further systematic study. Preliminary data suggesting that some patients with extremely rapid and chaotic mood fluctuations may respond to the L-type calcium channel blocker nimodipine are presented, and the theoretical implications discussed.

Abstract

To assess the effect of carbamazepine (CBZ) upon total serum cholesterol, we examined 38 inpatients with affective illness and one with multiple personality disorder who received a course of CBZ monotherapy. CBZ therapy yielded significant increases in total serum cholesterol that became evident during the second week of therapy, persisted throughout therapy, and reversed in the first few weeks after discontinuation of therapy. CBZ-induced increases in total cholesterol appeared independent of initial mood state, diagnostic subtype, baseline cholesterol or thyroid indices; CBZ levels, doses, and level-to-dose ratios; and the degree of change in mood and thyroid indices. CBZ induction of enzymes mediating cholesterol synthesis is a possible mechanism of the increase in total cholesterol observed with CBZ therapy. Although preclinical studies suggest possible influence of cholesterol on neurotransmitter regulation and behavior, clinical studies have yielded conflicting data. There are insufficient data to support a role for cholesterol in the anticonvulsant and psychotropic mechanisms of CBZ. The increase in total serum cholesterol seen with CBZ therapy is likely due to an increase in the high density lipoprotein fraction and is thus not likely to be clinically problematic in relationship to atherosclerosis.

Abstract

Twenty-three patients with complex partial seizures were evaluated with 18F-2-deoxyglucose positron emission tomography and with the Beck Depression Inventory. Five of 10 patients with left and zero of eight with right temporal electroencephalographic foci had depressive symptoms; one of five patients with poorly localized electroencephalographic foci also scored in the depressed range. Temporal, frontal, caudate, and thalamic normalized glucose metabolic rates among five patients with depressive symptoms and well-localized left temporal epileptogenic regions were compared with five patients without depressive symptoms but with similar electroencephalographic characteristics. Multifactorial analysis of variance yielded a significant nonlateralized mood by region interaction. Of nine individual regions compared, only inferior frontal cortex showed a significant difference in normalized regional metabolic rate between depressed and nondepressed patients. Metabolism in this region also distinguished patients with depressive symptoms from normal control subjects. Depressive symptoms in patients with complex partial seizures are associated with a bilateral reduction in inferior frontal glucose metabolism, compared with patients without depressive symptoms and normal control subjects. The frontal lobe hypometabolism observed in patients with depressions associated with epilepsy, Parkinson's disease, and primary affective disorder suggests that similar frontal lobe metabolic disturbances could underlie these conditions.

Abstract

GABAB mechanisms have been implicated in the antinociceptive, but not anticonvulsant effects of carbamazepine. A variety of antidepressants have been reported to upregulate GABAB receptors after chronic administration. The GABAB agonist l-baclofen was studied in depressed patients based on two separate rationales. l-Baclofen, in doses ranging from 10-55 mg/day, was administered to five patients with primary affective disorder. No patient showed a positive clinical response, while three patients showed a pattern of increasing depression or cycling during treatment and improvement during withdrawal. These preliminary data suggest that GABAB agonism is unlikely to produce antidepressant effects and may be unrelated to the mechanism of carbamazepine's antidepressant action. These data, taken with a reinterpretation of other findings that antidepressant modalities upregulate GABAB receptors in brain following chronic administration, suggest that GABAB antagonism rather than agonism may be a fruitful clinical strategy to explore in depression.

Abstract

Rapid cycling patients (greater than or equal to 4 episodes/year) often show inadequate response to lithium carbonate and are vulnerable to antidepressant-induced switches or cycle acceleration. Treatment with the anticonvulsant carbamazepine is now an accepted adjunct or alternative, and a series of uncontrolled studies also suggest the utility of valproate in this patient population. Clonazepam, suppressive doses of thyroid, calcium channel blockers, and other innovative treatments appear promising and deserve careful clinical investigation.